WO2025237965A2

WO2025237965A2 - Remotely controllable in-vivo robot system

Info

Publication number: WO2025237965A2
Application number: PCT/EP2025/063012
Authority: WO
Inventors: Sanjay MANOHARAN; Vivek Subramanian
Original assignee: Ecole Polytechnique Federale de Lausanne EPFL
Current assignee: Ecole Polytechnique Federale de Lausanne EPFL
Priority date: 2024-05-16
Filing date: 2025-05-13
Publication date: 2025-11-20
Anticipated expiration: 2026-11-16

Abstract

An intracorporeal robot (1) for deployment in a body tract, comprising: - a permanent magnet constituting an effector magnet (2) configured to be guided by an extracorporeal actuating magnet (105), and - a medical device (3) coupled to the effector magnet, the medical device comprising a shape memory structure (4) configured for tetherless actuation by an extracorporeal shape memory actuator (105).

Description

Remotely controllable in-vivo robot system

Field of the invention

The present invention relates to a system with an intracorporeal robot that can be guided through body cavities, vessels and tracts, particularly of the vascular or digestive system to execute intracorporeal procedures.

Background of the invention

Surgical interventions in body vessels and tracts are commonly needed in human healthcare. Ruptured organ walls, for example, from ulcers may require surgical repair. Aneurysms in arteries may require repair to prevent or close ruptures. Such procedures are typically addressed using either invasive or endoscopic/catheter-based surgical procedures.

An aneurysm is an abnormal dilation or bulging in a weakened area of a blood vessel, which can lead to a rupture and bleeding. Aneurysms can occur in any blood vessel but are most commonly found in the brain and aorta. Brain aneurysms are often located at the base of the brain in a region called the Circle of Willis, while aortic aneurysms frequently occur in the abdominal region. The incidence of aneurysm rupture varies by location and type but is estimated to be around 10% globally. The prognosis after a rupture depends on various factors, such as the size and location of the aneurysm, the patient's overall health, and the severity of the rupture. In the case of a ruptured brain aneurysm, subarachnoid hemorrhage can occur, which is a life-threatening condition that requires immediate medical attention. The mortality rate for subarachnoid hemorrhage is around 40%, and survivors often experience longterm disabilities. For a ruptured abdominal aortic aneurysm, immediate surgical intervention is required to repair the aneurysm. Following the rupture of an aneurysm, the prognosis is generally unfavorable, with a mortality rate of approximately 45% within the first 30 days. Additionally, only 40-50% of those who survive can achieve a positive functional outcome.

The traditional strategies for aneurysm repair include:

• Clipping, where a metal clip at the base of the aneurysm to prevent blood flow into the bulging area. One of the main drawbacks of this procedure is that it requires opening the skull or accessing the aneurysm through other means, which can be risky and invasive. Additionally, some aneurysms may not be accessible via clipping.

• Coiling - This minimally invasive procedure involves inserting a catheter into the artery and threading it up to the aneurysm. A coil made of metal wire is then placed inside the aneurysm to prevent blood flow. However, coiling may not be effective for certain types of aneurysms and may require repeat procedures or additional supporting devices.

• Flow diversion - This newer technique involves placing a stent-like device across the neck of the aneurysm, which redirects blood flow away from the bulging area. Flow diversion is a relatively new procedure, and long-term outcomes are still being studied. • Pipeline embolization device - Similar to flow diversion, this procedure involves placing a stentlike device across the neck of the aneurysm. However, the Pipeline device is designed to promote blood clotting inside the aneurysm, which eventually seals it off.

• Surgical excision - In some cases, the aneurysm may be removed entirely via surgical excision. However, this is typically only possible for aneurysms in certain locations and may be a very invasive procedure.

With respect to aneurysm occlusion devices and designs, several strategies have been previously described. US20120071911A1 describes a type of spherical helix shaped embolic coil that allows it to conform to the shape of the aneurysm and create a tight seal to prevent intra-aneurysmal blood flow. The coil can be made of a variety of materials, including shape-memory alloys, and can be coated with a material that promotes blood clotting to help seal the aneurysm. The spherical helix shape of the coil was designed to provide improved stability and occlusion compared to traditional linear coils.

A shape memory foam-based occlusion approach is disclosed in US9662119B2. The foam is inserted into the aneurysm and then heated to a temperature at which it expands to fill the aneurysm. The foam can be designed to have a specific shape and size, and can be coated with a material that promotes blood clotting to help seal the aneurysm. The device is intended to provide a minimally invasive treatment option for aneurysms that reduces the risk of complications associated with traditional surgical procedures.

US20150272589A1 discloses yet another aneurysm occlusion device that reexplored stent-assisted embolization by combining the meshing geometry of a traditional embolization coil and the restraining properties of an auxiliary stent in a single procedure. The device comprises a wire mesh structure that is coiled into the aneurysm, and a hemispherical mesh that is placed over the aneurysm to prevent blood flow into it. It includes a mechanism for deploying the mesh and stent simultaneously, allowing for efficient placement and occlusion of the aneurysm.

With reference to drug-based interventions for aneurysms, several patents have reported the incorporation of embolic agents in along with the occlusion device. However, shape memory-based drug delivery solutions are mostly confined to Shape memory actuators using a screw-ratchet drive or pumpdrive (W02009068250A8, US20130261595A1).

A list of designs for releasing therapeutic ingredients using shape memory, biodegradable polymers that can be implanted into a tissue has been described in US8158143B2. The drug of interest is encapsulated within a depot, which in turn is locked with a shape memory membrane. The diffusion property or membrane permeability could be modified by means of an external shape memory stimulus in order to discharge the drug. The design comprised of a single large rectangular reservoir or a series of reservoirs parallel to each other, covered by a shape memory barrier layer that controls the rate of release.

All the above treatment strategies rely on an endovascular catheter for their deployment. Catheters and other similar tethered occlusion device deployment strategies pose disadvantages in the form of limited maneuverability through complex geometries, increased risk of trauma due to the manual insertion and low accuracy.

With respect to repair of ruptures in organ walls, tissue engineering has become a topic of interest. Tissue engineering blends biology, engineering, and materials science to create artificial tissues for medical applications. It aims to repair or replace damaged tissues, offering innovative solutions for organ transplantation, wound healing, and regenerative medicine. This involves combining cells, scaffolds, and biologically active molecules to create functional biological substitutes for damaged or diseased tissues. A conventional method in tissue engineering involves culturing cells on a pre-fabricated material scaffold, resulting in a scaffold-cell. Following an in vitro proliferation phase, this composite is transplanted into the patient's body invasively. Through the progressive degradation and assimilation of biomaterials within the physiological environment, the introduced cells persist in proliferating, differentiating, and generating extracellular matrix. Ultimately, this process culminates in the desired outcome of repairing and functionally reconstructing tissues or organs. Earlier, these scaffolds were fabricated with conventional manufacturing techniques. However, recently with the advent of 3d printing the scaffolds are additively fabricated and more personalized to the patient and several, additive fabrication strategies exist for the same.

3D bioprinting nonetheless exhibits inherent limitations. Developing functional tissue in-vitro with a bioreactor and then invasively implanting these fragile constructs in-vivo presents a formidable challenge. It is associated with contamination risks, requirement for an invasive operation and above all rejection by the recipient's body. Researchers within this field encounter a multitude of challenges as they strive to overcome these intricacies. To address the challenges, in-situ bioprinting has emerged as a transformative paradigm in the medical field. This approach involves the direct deposition of bioink within damaged tissue within the human body. A pivotal advantage of this method lies in the obviation of an artificial micro-environment for printing, as the human body itself functions as the in-vivo bioreactor. The conceptualization of in-situ bioprinting was initially presented by Phil G. Campbell and Lee E. Weiss from Carnegie Mellon University in 2007, employing inkjet technology.

Scientists at the Wake Forest Institute for Regenerative Medicine in 2018 published an article on In-Situ Bioprinting of Autologous Skin Cells Accelerates Wound Healing of Extensive Excisional Full Thickness Wounds. This article elucidated the design and substantiated a proof-of-concept for a bedside skin bioprinting system. This system seamlessly incorporates imaging data acquired through a self- positioning handheld laser scanner to delineate the topography of a wound. Subsequently, it facilitates in-situ cell delivery, tailoring the technology to the specific needs of individual patients. The devised apparatus demonstrated the ability to print skin cells directly into a wounded site, administering dermal fibroblasts and epidermal keratinocytes to designated locations within the wound.

In a similar effort in 2023, engineers at the Moscow Oncology Research Center disseminated a scientific article detailing a Commercial Articulated Collaborative In Situ 3D Bioprinter designed for skin wound healing applications. The apparatus featured an electric motor-driven extruder for hydrogel extrusion, affixed to a KUKA robotic arm. Connectivity between the computer and the end effector was established via USB, while the computer and the robot controller communicated through the Transmission Control Protocol/Intemet Protocol (TCP/IP). Notably, the system incorporated a real-time breathing skin displacement sensor to enhance the precision of hydrogel component deposition.

A ferromagnetic Soft Catheter Robotic system (FSCR) for minimally invasive bioprinting was described by Zhou et al., in 2021. It employed magnetic actuation of a catheter body that dispensed biomaterials to achieve minimally invasive in vivo bioprinting. The catheter body was functionalized with hard- magnetic particles and was operated laparoscopically with magnetic control. The FSCR demonstrated the ability to print different patterns using multiple inks including the printing of functional hydrogel on tissue phantoms and live rat livers in a minimally invasive manner.

Researchers at Inserm, France in 2020 demonstrated a laser-induced forward transfer (UIFT) effect. UIFT-based bioprinting strategy for in situ printing of mesenchymal stromal cells in a calvaria bone defect model in mice, and it was shown to favor bone regeneration. Here a pulsed laser source was employed to direct energy onto a donor substrate containing the bioink and bioprinting was demonstrated on anesthetised mice. It should be noted that an incision in the middle of the skull, from the nasal bone to the superior nuchal line, was performed in order to expose the calvaria.

Chen et al., from Sichuan University in 2020 developed a 3D bioprinting technology based on digital near-infrared (NIR) photopolymerization (DNP) that allowed for non-invasive in-vivo 3D bioprinting of tissue constructs. In this methodology, a digital micromirror device modulates NIR into customized patterns, dynamically projecting it to spatially induce the polymerization of subcutaneously injected monomer solutions functionalized with a nano-initiator for providing up-conversion UV photons required for polymerization.

In summary, the current in-situ bioprinting technology involves huge bed-side mounted and invasive surgical robotics or optical methods - laser-based material transfer or digital micromirror device based bioprinting for three-dimensional bioprinting tissue grafts. In case of the former, the repertoire of procedures and accessible points remain limited to dermal or intraperitoneal constructs. In case of the latter, deep body bioprinting has been achieved through large incisions are performed to gain access.

Summary of the invention

It is an object of this invention to provide a system for in-vivo medical procedures carried out in body tracts, in particular the vascular or digestive tracts, that is minimally invasive and easy to deploy.

An application specific object of the invention is to provide a system for in-vivo aneurysm treatment procedures that is minimally invasive and easy to deploy.

An application specific object of the invention is to provide a system for in-situ bioink administration or patterning procedures, in particular in vascular or gastro-intestinal tracts, that is minimally invasive and easy to deploy.

An application specific object of the invention is to provide a system for in-vivo tissue or liquid biopsy collection in body tracts that is minimally invasive and easy to deploy.

Objects of the invention have been achieved by providing a remotely controllable intracorporeal robot according to the independent claims.

Dependent claims set forth various advantageous embodiments.

Disclosed herein is an intracorporeal robot for deployment in a body tract, comprising: a permanent magnet constituting an effector magnet configured to be guided by an extracorporeal actuating magnet, and a medical device coupled to the effector magnet, the medical device comprising a shape memory structure configured for tetherless actuation by an extracorporeal shape memory actuator.

In an advantageous embodiment, the shape memory structure comprises a wire structure.

In an advantageous embodiment, the wire structure comprises a coil.

In an advantageous embodiment, the wire structure is configured to transform into a filament bundle upon shape memory actuation.

In an advantageous embodiment, the shape memory structure comprises a petaloid structure. In an advantageous embodiment, the shape memory structure has a shape with an outer envelope having a first volume prior to shape memory actuation and a second volume after shape memory actuation, the second volume being greater than the first volume.

In an advantageous embodiment, the intracorporeal robot is configured for aneurysm treatment.

In an advantageous embodiment, the medical device comprises an active therapeutic substance.

In an advantageous embodiment, the active substance is coated on the shape memory structure or contained in a container of the medical device, the container configured for actuation from a closed configuration to an open configuration by actuation of the shape memory structure.

In an advantageous embodiment, the medical device comprises a payload coupled to the shape memory structure, the payload comprising any one or more of : a drug delivery device, a sample collection device, a bioink dispensing device or a surgical tool.

In an advantageous embodiment, the medical device comprises a payload including a container with a plunger or flexible wall, and a spring applying pressure on the plunger or flexible wall.

In an advantageous embodiment, the container comprises a therapeutic substance and the spring is configured for applying a positive pressure on the active substance contained in the container upon shape memory actuation of the medical device, for dispensing the therapeutic substance out of the container.

In an advantageous embodiment, the container comprises an internal bore with a diameter gradient configured to control a spring rate of the spring.

In an advantageous embodiment, the medical device is a sample collection device and the spring applies a negative pressure on the plunger or flexible wall of the container configured to generate a negative pressure within the container to draw in liquid into the container upon shape memory actuation of the medical device.

In an advantageous embodiment, the shape memory structure comprises a trigger mechanism blocking movement of the spring, the trigger mechanism being releasable upon shape memory actuation to allow the spring to displace the plunger or flexible wall of the container.

In an advantageous embodiment, the trigger mechanism comprises a restraining element. The restraining element may comprise a circlip or a transverse beam or another form of blocking element.

In an advantageous embodiment, the shape memory structure comprises or consists of a bioresorbable polymer.

In an advantageous embodiment, the bioresorbable polymer is selected from a group consisting of polylactic acid (PLA), polyurethane (PU), poly(s-caprolactonc) (PCL), polydioxanone (PDO), and copolymers thereof.

In an advantageous embodiment, the polymer is doped with melanin in a volume percentage range between 1 and 12%, preferably between 4 and 12%.

In an advantageous embodiment, the shape memory structure is configured for electromagnetic actuation, preferably by radiation in a near infra-red range having a wavelength range from 760 nm to 1500 nm.

In an advantageous embodiment, the medical device is configured for drug delivery in a body tract.

In an advantageous embodiment, the medical device is configured for dispensing an active substance on a wall of a body tract, for instance a hemostatic agent in gastrointestinal medical applications.

Also disclosed herein is a remotely controllable in vivo robot system comprising the intracorporeal robot of any preceding embodiment, and an extracorporeal actuator system including an actuating magnet and a shape memory actuator.

In an advantageous embodiment, the extracorporeal actuator system comprises a multi-axis robot arm, the actuating magnet mounted on the multi -axis robot arm.

In an advantageous embodiment, the actuating magnet comprises a permanent magnet displaceable around a patient support table by the robot arm.

In an advantageous embodiment, the shape memory actuator comprises a near infra-red source.

In an advantageous embodiment, the system is configured for extruding a therapeutic material by guiding the intracorporeal robot in a body tract and actuating the shape memory structure by activation of the shape memory actuator and steering the intracorporeal robot such through predetermined paths such that the therapeutic material is deposited in accordance with the predetermined paths. In an advantageous embodiment, the system is configured for biopsy collection by guiding the intracorporeal robot in a body tract and actuating the shape memory structure by activation of the shape memory actuator.

In an advantageous embodiment, the system is configured for occlusion of an aneurysm sack by guiding the intracorporeal robot in a body tract into the aneurism sack and actuating the shape memory structure by activation of the shape memory actuator.

Also disclosed herein, according to an aspect of the invention, is a method for repairing a hemorrhage site in a tissue or organ, the method comprising: providing a remotely controllable in vivo robot system comprising an intracorporeal robot and an extracorporeal actuator system including an actuating magnet and a shape memory actuator (105), wherein the intracorporeal robot comprises a permanent magnet constituting an effector magnet configured to be guided by the actuating magnet, and a medical device coupled to the effector magnet, the medical device comprising a shape memory structure, configured for tetherless actuation by the shape memory actuator, wherein the shape memory structure comprises a trigger mechanism and the medical device comprises a payload including a container with a plunger or flexible wall, and a spring applying pressure on the plunger or flexible wall, wherein the trigger mechanism is configured to block movement of the spring, the trigger mechanism being releasable upon shape memory actuation to allow the spring to displace the plunger or flexible wall of the container; injecting the intracorporeal robot into a body of a patient, preferably orally; applying an external magnetic field outside the body of the patient using the actuating magnet to magnetically guide the effector magnet of the intracorporeal robot in a body track of the patient to the site of the hemorrhage; and applying an external trigger using the shape memory actuator configured to cause a shape deformation in the shape memory structure such that the trigger mechanism is released to unblock the movement of the spring, wherein an active therapeutic substance is extruded out of the container onto the site of the hemorrhage upon the shape deformation to at least partially seal said hemorrhage. In an advantageous embodiment, the method further comprises steering the effector magnet using the actuating magnet through predetermined path such that the active therapeutic substance is deposited in accordance with the predetermined path.

In an advantageous embodiment, the extracorporeal actuator system comprises a multi-axis robot arm, the actuating magnet mounted on the multi-axis robot arm, wherein the actuating magnet may comprise a permanent magnet displaceable around a patient support table by the robot arm.

In an advantageous embodiment, the shape memory structure comprises or consists of a bioresorbable polymer, wherein the bioresorbable polymer may be selected from a group consisting of polylactic acid (PLA), polyurethane (PU), poly(s-caprolactone) (PCL), polydioxanone (PDO), and copolymers thereof, and wherein the polymer may be doped with melanin in a volume percentage range between 1 and 12%, preferably between 4 and 12%.

One implementation of the present invention is configured for preventing aneurysm rupture and for promoting aneurysm obliteration. An occlusion intracorporeal robot fabricated with an in-vivo transient, shape memory material is tetherlessly steered to the aneurysm site through an applied external magnetic field in its shape memory programmed state. The intracorporeal robot in its shape memory programmed state will assume a smaller footprint to promote easy endovascular navigation. Upon reaching the aneurysm site, the shape memory of the intracorporeal robot is triggered to assume a sac-occlusive configuration that isolates the aneurysm sac from the parent artery. An example of the said sac-occlusive design may be a spring body with petaloid arms on both ends. The petaloid arms can obstruct blood flow at the aneurysm neck while the uncompressed spring can help stabilize the structure against the blood flow by exerting a counter force. The spring body might consist of one or more variations, including helical, serpentine, wave springs, or other configurations designed to compress and decompress programmably.

The intracorporeal robot apart from providing mechanical obstruction from the parent artery flow may initiate drug-induced thrombosis within the aneurysm for a stable post-procedural sealing through therapeutic agents. These therapeutic agents may be incorporated in the intracorporeal robot to enhance the thrombus reorganization which in turn decreases the chances of embolization. Therapeutic agents may be thrombus organization promoters or of hemostatic nature and may be discharged or exposed to the intra-aneurysmal environment from the uncompression of the telescopic microcapsule during the shape recovery process. Additionally, the therapeutic agent may also be imbued in the shape memory material or be placed bare inside the spring body. In one example, regenerated oxidized cellulose incorporated into the intracorporeal robotic system has been used to achieve ~1.4x coagulation times in in-vitro tests with ex-vivo recalcified bovine blood.

In another implementation of the invention, the intracorporeal robot does not comprise an occlusion design and the shape memory spring constrained microcapsule-based drug delivery alone is used for the delivery of radiotherapeutics or chemotherapeutics for other drug -delivery requirements. Furthermore, through the utilization of a two-way material the capsule may be pulsatively opened and closed by alternating the shape memory stimulus to accomplish a sustained release, site-specific or a timedependent release.

The concept of tetherlessly actuated shape memory occlusion may be manifested in the form of shape memory coil which in its programmed state remains wound over a carrier actuatable with an external magnetic field. Upon shape recovery, the wound coil may recover inside the aneurysm sac resulting in occlusion. In addition, therapeutic agents may be incorporated or intertwined into the coil to induce and enhance the thrombus reorganization as described previously.

In another embodiment, the coiling may be replaced with a shape memory foam impregnated into the foam to assume a sac occlusive configuration and to induce thrombus formation and reorganization.

A different medical application of the present invention introduces a intracorporeal robotic bioink dispenser or pattemer engineered to extrude biomaterials or bioinks either cell-less or cell-laden, assisting in sealing perforations or breaches in various tissues. Potential physiological environments maybe as intestinal, bladder, lung, vascular, liver, cardiac, abdominal, and other soft tissues. This variation features a dispenser assembly equipped with a spring-loaded mechanism utilizing a shape memory polymer spring piston, supplemented by an integrated magnet. The magnet can be manipulated using an external magnetic field to guide it to the desired location. Furthermore, an external light trigger is employed to activate the spring mechanism, prompting the piston to expel the material stored within the dispenser. The material may be a cell-less, cell-laden, contain one or more therapeutic agents or a combination of both therapeutics and cells on a biomaterial. A suitable biomaterial may be collagen, gelatin, and silk fibroin, polysaccharides like chitosan and alginate, synthetic polymers including polyethylene glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA), as well as natural polymers like decellularized extracellular matrix (ECM) and nanocellulose. Bioactive ceramics like bioactive glass and calcium phosphate are also potential but not limiting options. Hydrogels, synthetic polymers, and polysaccharides further contribute to the diverse range of materials. These materials may or may not be blended with cell adhesion molecules like RGD peptides (Arg-Gly-Asp), Fibronectin, Laminin, Collagen, Vitronectin, Poly-L-lysine, Poly-D-lysine, Hyaluronic acid, Integrin-binding peptides, Polyarginine etc., to promote cell growth and migration. The intracorporeal robot dispenser may be used to discharge the biomaterial and may be steered to create a pattern of appropriate shape, position, and size to cover the lesion, facilitating healing and closure.

An intracorporeal robot-based system according to the invention excels over traditional methods due to the ability to navigate through complex and deep biological environments with level-one invasiveness, minimal tissue disturbance and reduced infection risk.

The present invention encompasses medical device technology, surgical methodologies, and in-situ bioprinting. It centers on intracorporeal robot configurations built using shape memory polymers that are navigated through the physiological environments with magnetic fields. The shape memory programmed into these structures are responsive to external stimuli, which results in a conformational change of the intracorporeal robot. The conformational change may be harnessed to execute specific intracorporeal objectives, whether surgical or related to in-situ bioprinting.

Various advantageous aspects of the intracorporeal robot according to embodiments of this invention may thus be realized, including

- an intracorporeal robot that combines tetherless actuation, shape memory-based occlusion, and a drug release capacity conducive to intra-aneurysmal thrombosis, thereby enhancing the likelihood of aneurysm obliteration.

- an intracorporeal robot that incorporates tetherless actuation coupled with a dispenser for ejecting tissue scaffold material, enabling in-situ bioprinting for tissue regeneration in diverse physiological environments, including vascular, gastrointestinal, neurological, or orthopedic contexts.

- an intracorporeal robot that facilitates the precise deposition of drug-laden scaffolds, offering capabilities such as localized chemotherapy, antimicrobial therapy, hemostatic therapy, and interventions in reproductive or gynecological domains, thereby minimizing systemic exposure.;

-an intracorporeal robot that employs cell-laden scaffolds for pancreatic Islet Transplantation and other analogous in-situ therapeutic production applications with specific cell-laden scaffolds; and

- an intracorporeal robot that serves as a delivery platform for establishing organ interfaces in neural and gastrointestinal settings, as well as for conducting tissue biopsies.

Brief Description of the drawings

Figure 1 are photographs of experimental setups of a remotely controllable in vivo robot system according to embodiments of the invention; Figure 2a is a schematic illustration of a shape memory material formulation comprising polylactic acid blended with melanin;

Figure 2b is a plot of shape recovery properties of a V-shaped construct made of the material of Figure 2a with different percentages of melanin;

Figure 3 is a schematic illustration of an intracorporeal robot according to an embodiment of the invention, Figure 3A illustrating a shape prior to actuation, Figure 3B illustrating the shape just after being actuated, and Figure 3B illustrating two variants of an intracorporeal robot with an actuated shape memory structure, one without a payload and the other with a payload in the form of a drug container;

Figure 4 is a schematic illustration of an intracorporeal robot being deployed for treatment of an aneurysm according to an embodiment of the invention;

Figures 5a and 5b are schematic illustrations of intracorporeal robots according to embodiments of the invention, showing different payload spring actuation designs;

Figure 6 is a schematic illustration of an intracorporeal robot according to another embodiment of the invention

Figure 7 is a schematic illustration of an intracorporeal robot being deployed for treatment of an aneurysm according to an embodiment of the invention;

Figure 8 is a schematic illustration of the sequential steps for intracorporeal robot to dispense bioink according to an embodiment of the invention;

Figure 9a is a schematic illustration of a tetherlessly controllable in-vivo robot system comprising an intracorporeal robot for patterning bioink according to an embodiment of the invention;

Figure 9b is a photograph of an experimental setup of a remotely controllable in vivo robot system according to an embodiment of the invention comprising an intracorporeal robot for printing bioink;

Figure 10 are photographs of an experimental setup of a remotely controllable in-vivo robot system according to an embodiment of the invention comprising an intracorporeal robot for printing gastric fibroblast-laden bioink followed by fluorescence imaging with Calcein-AM;

Figure 11 presents a schematic depiction of an intracorporeal robot, as per one embodiment of the invention, demonstrating the control of spring rate for achieving sustained dispensing via a barrel with a diameter gradient;

Figure 12a is a schematic illustration of one embodiment wherein an intracorporeal robot may be used to apply a hemostatic sealant over an active haemorrhage site in a bodily cavity.

Figure 12b are plots illustrating the blood flow rate after sealant administration via robot and the application of pressure over the hemorrhage site by decreasing the EM-AM distance;

Figure 13a is a schematic illustration of the sequential steps for an intracorporeal robot to collect a liquid biopsy sample according to an embodiment of the invention;

Figure 13b is a schematic illustration of a remotely controllable in vivo robot system with the intracorporeal robot of Figure 13a for collecting a sample being deployed according to an embodiment of the invention; Detailed Description of the invention

Referring to the figures, a remotely controllable in vivo robot system 100 according to embodiments of the invention comprises an extracorporeal actuator system 102 and an intracorporeal robot 1 configured to be displaced and actuated in vivo by the extracorporeal actuator system.

The intracorporeal robot 1 comprises a medical device 3 coupled to a magnet named herein an effector magnet (EM) 2 configured to displace and guide the medical device under the influence of an external magnetic field.

Depending on the medical application, the medical device 3 comprises one or more functional medical elements, the functional medical element comprising any one of: an occlusion structure 3a, a bioink dispensing device 3b, a drug delivery device 3c, a sample collection device 3d, a surgical tool.

The medical device 3 comprises a shape memory structure 4 which may either form all or part of the functional medical element, or which may consist of or comprise a trigger mechanism 5 configured to actuate the functional medical element.

The shape memory structure 4 is configured for remote (i.e. tetherless) actuation through body tissue by electromagnetic or acoustic energy transmission. In an advantageous embodiment, the shape memory structure 4 is configured for actuation by electromagnetic emissions in the optical domain, in the near to middle infrared range, which is in a wavelength range from 760 to 3000 nm (10'⁹m), preferably in the near infrared (NIR) range, which is in a wavelength range from 760 to 1500 nm.

The extracorporeal actuator system 102 according to embodiments of this invention, comprises an actuating magnet (AM) 104 to generate an external magnetic field that displaces the effector magnet (EM) 2. The actuating magnet 104 may be mounted on a robot arm 103 for displacing the actuating magnet around a patient support table. The actuating magnet may either be a permanent magnet that may be displaced in translation spatially by the robot arm and as required, angularly in order to orient the magnetic field and vary the magnetic field intensity on the effector magnet to provide spatial guidance of the effector magnet in the patient’s body tract. Instead of a permanent magnet, the actuating magnet may also comprise an electromagnet system.

The extracorporeal actuator system 102 further comprises a shape memory actuator 105. The shape memory actuator is configured to remotely actuate the shape memory structure 4 and as mentioned above may be configured for emission of electromagnetic radiation, or acoustic transmission for actuation of the shape memory structure. The shape memory actuator 105 in preferred embodiments comprises an optical emitter in the near to middle infra-red range. It may however be noted that the remote actuation of shape memory materials may also occur under other wireless stimuli such as under magnetic fields.

The medical device 3 may further comprise a payload 10 coupled to the shape memory structure 4 and thus also to the effector magnet 2. The payload may have different forms or comprise different elements or mechanisms depending on the medical application and function of the memory device 3.

It may however be noted that in certain embodiments, the shape memory structure 4 performs the function of the medical device 3 such as forming an occlusion structure 3a, or acting as a surgical tool 3e, without any additional payload.

In certain applications however, the payload may comprise various elements such as a carrier or support structure, a drug delivery device 3c, a biopsy collection device 3d, a bioink printer device 3b, a surgical tool 3e and an active substance 22 that may be provided in a container 16.

For instance, in the embodiments illustrated in figures 3d, 4a to 4e and figure 5, the medical device comprises a shape memory structure 4 and a payload 10 comprising a drug delivery device 3c including a container within which an active substance 22 is contained. Upon actuation of the shape memory structure 4, the drug delivery device is actuated by opening of the drug container and release of the active substance. Release of a drug in situ may therefore be effected by actuation of the shape memory structure 4.

In the embodiments of figure 8, the payload comprises a dispensing device 3b in the form of a bioink printer having a container 16 filled with a bioink, the container comprising a plunger 18 or a collapsable flexible container structure upon which a spring 14 applies pressure to extrude bioink out of an orifice 20 of the container 16. The spring may either be in the form of a shape memory structure that deploys and exerts pressure upon actuation of the shape memory material or may be a non-shape memory material that is in a pre-stressed compressed state and held in that state by a trigger mechanism 5 forming the shape memory structure, and that can be actuated to release the pre-stressed compression spring. The shape memory structure may for instance comprise a circlip, a bent traverse beam, and various other shapes that engage and block the pre-stressed compression spring in its pre-stressed state prior to actuation, and upon actuation of the shape memory the change in shape of the traverse beam, circlip or other element disengages from a shoulder holding the compression spring to release actuation of the bioink dispensing.

In cases where a liquid biopsy sample collection device 3d has to be deployed for biopsy collection as illustrated in figure 13a or 13b, a similar mechanism may be utilized where a spring - plunger construct is expanded past its free length and locked in place with an NIR-stopper. Upon trigger the robot platform may retrieve liquid biopsies through expansion of barrel 16 volume via the spring returning to its free length. Alternatively, the stopper mechanism maybe avoided and replaced with a shape memory structure that generates the force required to increase the volume of the barrel.

According to one aspect of the invention, the medical device comprises an occlusion structure 3a for aneurysm treatment as illustrated for instance in figures 3 to 5. In these embodiments, the medical device comprises a shape memory structure that includes a spring mechanism 9 and a petaloid structure 7 that is initially in a folded compressed state as illustrated in figure 3a and that may be actuated by actuation of the shape memory structure such that the petaloid arms fan outwardly and the spring mechanism 9 expands so as to increase the volume envelope occupied by the medical device 3.

The effector magnet 2 may be comprised within the structure of a payload 10 that may further comprise a container comprising an active substance 22 that is released in the aneurysm treatment site upon shape memory actuation of the shape memory structure 4. Such active substance 22 may for instance be configured for blood clotting and other functions for obturation of the aneurysm.

The medical device may comprise bioresorbable materials that are resorbed in the patient’s tissue whereby the effector magnet may comprise magnetic articles within a bioresorbable material. In a variant, the effector magnet may be coupled to the medical device in a releasable manner and once the medical device is at the site of treatment, the effector magnet may be released by a shape memory structure trigger mechanism and guided out of the site of treatment, through the body tract for extraction out of the body, for instance through the site of introduction.

In certain embodiments of a medical device with an occlusion structure 3a for aneurysm treatment, the shape memory structure 4 may comprise a filament or wire structure 6 that is provided in a compact wound form for transport of the intracorporeal robot to the treatment site, and upon actuation by the shape memory actuator 105 transforms to a filament bundle occupying a large volume to occupy the aneurysm sac. The filament may be coated with an active therapeutic substance that promotes blood clotting and other functions for building of tissue in the aneurysm sac.

It may be noted that the payload 10 and/or shape memory structure 4 may comprise a surgical tool such as a micro-clamp or a hook mechanism that clamps or stiches a section of tissue, particularly a section of wall of the body tract. The surgical tool may also comprise a cutting instrument, for instance in the form of scissors, actuated by the actuation of a shape memory structure 4 to cut a section of tissue, for instance for collection of a non-liquid tissue sample. The intracorporeal robot navigation and its objective execution may thus be achieved through a combination of a magnetics-based steering strategy, materials used in the intracorporeal robot structure construction and external application of a shape memory stimulus.

Magnetic navigation is per se known and may be based on manoeuvring a micro-magnet-based device in a desired workspace through two main modalities - electromagnetic and permanent magnet-based systems. Electromagnetic systems, utilize coils, allow for complex field generation, while permanent magnetic systems provide energy-efficient alternatives. Each system has its advantages and limitations, impacting factors such as degrees of freedom (DoF) and workspace. In both the modalities, motion control in magnetic steering has been accomplished through Open-loop control methods where preprogrammed instructions and teleoperation, provide initial characterization but lack adaptability. Closed-loop control methods, employing proportional-derivative (PD) controllers for holonomic microrobots and velocity-independent control laws for non-holonomic ones, ensure precise motion, especially crucial in environments with perturbations and limitations.

Upon steering the intracorporeal robot to the target location, the shape memory structure may be triggered (actuated), whereby optical actuation is advantageous. By choosing the appropriate wavelength of light, an external light source can be shone on the body to drive triggering of the intracorporeal robot within the patient’s body.

It is per se known to trigger shape memory functionality within a body using Near Infrared Light (NIR) as described in the paper titled “A near-infrared light-triggered shape-memory polymer for long-time fluorescence imaging in deep tissues”, which described an in-vitro simulation of NIR-triggered shapememory stent deployment in a rat carotid artery. A NIR shape-memory polymer was developed by crosslinking 6-arm polyethylene glycol)-poly(8-caprolactone) using a croconate dye YHD798. Further, another paper titled, “Natural Melanin/Polyurethane Composites as Highly Efficient NIR- Photoresponsive Shape Memory Implants”, described a NIR shape memory composite that could be implanted in the fallopian tube for the purpose of contraception with an experimental demonstration in rats.

More details on specific examples are provided hereinafter with reference to the figures.

Figure 1 represents some example arrangements of the components necessary for navigation and shape memory stimulation of the intracorporeal robot within different simulated biological environments such as the vascular system or gastrointestinal system. In general, all the setups feature a robotic arm attached with a to the actuating magnet (AM) that serves to manipulate the positioning of the effector magnet (EM) contained within the intracorporeal robot, relative and the substrate which could either be glass (Figure 1A), a silicone vascular model (Fig IB) or a silicone gastric model (Figure 1C). The AM positioned next to the substrate, produces a magnetic field that draws the EM upward from the bottom, and sticks to the top of the substrate. Subsequently, when the robotic arm follows predetermined patterns of movement which in turn induces controlled motion of the EM. Various parameters such as EM-AM distance, AM velocity, AM geometry, AM polarity, EM payload, viscosity of the surrounding fluid, flow velocity of the fluid, coefficient of friction of the substrate and elasticity of the substrate affect the maneuverability of the EM in various environments.

As for the material system involved in the intracorporeal robot, a single shape memory material or a blend of shape materials or a blend of a shape memory material and an external stimulus responsive agent maybe used. For instance, shape memory polymers or alloys that respond to temperature, light, electric fields, magnetic fields, moisture or chemical stimuli fabricated from single or multiple materials. One example of such a blend that is responsive to external stimulus can be a shape memory material that responds to NIR irradiation. NIR can be used since it can penetrate biological tissues due to its longer wavelengths and is thus less scattered or absorbed by tissues. This allows it to travel deeper into the tissue, which is important for various biomedical applications. An example for such a shape memory material, maybe a widely available biocompatible and in vivo biodegradable, shape memory polymer like Polylactic acid, Polyurethane or Polycaprolactone combined with an optimized weight % of an NIR photothermal conversion material. The photothermal component of the shape memory polymer can convert the incident light into heat and trigger shape memory. Some suitable candidates for the photothermal component include gold nanoparticles, black phosphorous, certain organic dyes or other natural pigments like melanin. The contraption may also be fabricated using a shape memory alloy interfaced with the NIR photothermal component for in vivo shape recovery. The material system may be chosen with an emphasis on in vivo biodegradation since the intracorporeal robot is expected to be in vivo transient. Lastly, the shape memory system may also be mixed with some radiopaque materials to help with radio imaging during deployment. One formulation that was developed during the testing of the current invention was polylactic acid blended with 6 weight % melanin. These materials were selected for their biocompatibility and in vivo biodegradability. Melanin serves as the photothermal element aiding in the shape recovery properties of polylactic acid whose Tg is around 55 to 60 degrees Celsius. This low Tg helps with quick shape recovery after NIR irradiation. The formulation and shape recovery properties are illustrated in Figure 2

Figure 3 shows an embodiment of a intracorporeal robot architecture in A) Programmed state with a closed capsule and retracted arms B) The contraption starts to recover under NIR stimulus C) In the occlusion-only embodiment, the spring is uncompressed and the arms assume the neck obstructing configuration thereby cutting off the blood flow into the aneurysmal sac D) In the occlusion-drug discharge embodiment After recovery, the arms open up and the spring is uncompressed, the telescopic parts of the capsule open and hence the drug/therapeutic agent exudates. The other telescopic part contains an actuatable carrier like an effector magnet that can be controlled using an external actuating magnet. Various parameters of the actuating and effector magnet can be optimized to achieve stable and predictable manoeuvrability within commonly encountered vascular architectures like bifurcations, kinks, loops and tortuosities. The presence of an effector magnet may also help with radiopacity for imaging during the occlusion device deployment. The magnet may be made of a variety of materials. The choice of materials is preferably made based on biocompatibility and magnetic properties. Examples of possible magnetic materials include but are not limited to blah, iron, cobalt, nickel, gadolinium, magnetite, aluminum, platinum, manganese, bismuth, copper, Alnico (Aluminum, Nickel, Cobalt), Samarium Cobalt (SmCo), Neodymium Iron Boron (NdFeB), silicon steel, permalloy (Nickel- Iron alloy), amorphous metals, and superparamagnetic iron oxide nanoparticles. However, the current invention was tested with N52 grade NdFeB for both AM and EM due to its relative biocompatibility and high magnetic strength, evident from their high magnetic flux density (B) and field strength (H), coupled with impressive coercivity (He) and remanence (Br), surpassing other materials.

Figure 4 illustrates the process of occlusion and drug release resulting in intra-aneurysmal thrombosis A) shape memory programmed intracorporeal robot is magnetically guided into the aneurysm and a shape recovery stimulus is applied B) Post-stimulus the device fully recovers its native configuration thereby causing a mechanical obstruction leading to exclusion of the aneurysm from systemic pressure and intra-aneurysmal partial hemostasis. Further, the microcapsule opens and releases the drug/drug- combination causing quick thrombosis under partial hemostasis C) Intra-aneurysmal clot formation and the accompanied by subsequent wound healing processes extracellular matrix by the fibroblasts D) The intracorporeal robot being in vivo transient degrades within the body and F) Post procedural aneurysm shrinkage is expected after a few weeks. Finally, the intracorporeal robot design may not be limited to the described example. A non-exhaustive list of examples for alternative spring-like design for the body and an alternative petaloid arm design for the intracorporeal robot are illustrated in Figure 5. The microcapsule maybe fabricated with the same shape memory material or any other commonly used capsule materials that are both biocompatible and biosorbable such as polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), chitosan, or gelatin.

An example of a shape memory drug-delivery intracorporeal robot without an occlusion function is depicted in Figure 6. It may be tetherlessly navigated magnetically to the desired site like the previous embodiments. In combination with a two-way shape memory material such as Nickel-Titanium (NiTi) alloys, Polyurethane-based, Epoxy-based, or Polyvinyl alcohol-based Shape memory polymers etc., Upon withdrawal of the stimulus the intracorporeal robot goes back to its native configuration. This property arising from an intermittent shape memory stimulus may be used to achieve a pulsated drug release or exposure. Furthermore when a radiotherapeutic is utilized inside the capsule, is implanted at a desired site following magnetic steering, the shape memory stimulus can be pulsated to achieve intermittent radiation exposure therapy for tumors in different regions, arteriovenous malformations (AVMs), Keloids, Graves' disease, Dupuytren's contracture, Macular degeneration, Pain management for bone metastases etc., Notably, this strategy could be an alternative for radiotherapeutic seeds and pellets implanted by conventional invasive methods.

Figure 7 depicts an example of a tetherless, shape memory-based coil embolization technique. The shape memory coil is programmed to be wound to an actuatable carrier. Upon shape recovery, the wound coil can recover inside the aneurysm sac resulting in occlusion. Additionally, figure 7 also illustrates an example of a mode in which a therapeutic agent may be incorporated or intertwined into the coil to induce and enhance the thrombus formation/reorganization. Similarly, the shape memory coil can be replaced with a compressed shape memory foam that may recover inside the aneurysmal sac resulting in occlusion. In the presence of embedded therapeutic agents, the foam may also promote and enhance thrombus formation/reorganization as mentioned previously. The therapeutic agents may be Chitosan, Cellulose-based materials (regenerated oxidized cellulose), Gelatin-based materials, Synthetic hemostatic materials, Fibrin sealants.

Figure 8 illustrates a design of a intracorporeal robot dispenser intended for extruding a therapeutic material such as a bioink for cell-free or cell-laden tissue scaffolds. This intracorporeal robot dispenser resembles a syringe, comprising a barrel and a piston. However, the piston mechanism differs; it is connected to a conventional compression spring at its shut length and is secured by a shape memory rod passing through a hole in the piston, functioning as a stopper. Additionally, akin to the previously described aneurysm occlusion model, it incorporates an effector magnet (EM) to aid magnetic steering. Notably, this magnet is ring-shaped, with its inner diameter serving as the nozzle for extruding the contents of the barrel. Upon triggering the stopper using a near-infrared light source, it retracts and allows for the spring to reach its free length and hence the barrel contents are extruded from the dispenser. By steering the effector magnet through predetermined paths using the using an external actuating magnet attached to a robotic arm, material deposition in set patterns maybe achieved.

The barrel maybe constructed out of a biocompatible and non-bioirritable material with a low coefficient of friction with respect to the navigating physiological environment. Furthermore, it is essential to consider the material's stability across diverse physiological conditions, such as variations in pH, enzymatic activity and temperature. On that regard, materials such as Glass, High Density Polyethylene, Polyether Ether Ketone (PEEK), Polypropylene, Polytetrafluoroethylene are good candidates Depending on the rheological properties of the material to be extruded and the nozzle diameter, the spring specifications such as spring index, number of active coils and bulk modulus of the material maybe varied to achieve optimal results. The material involved in the spring construction need not be biocompatible since the material is hidden from the physiological environments. On that regard, during the invitro testing of this invention, a barrel and the plunger were fabricated from a biocompatible resin from LIQREATE™ Bio-Med Clear was used. It allows for manufacturing biocompatible end-use parts that can be sterilized by steam sterilization in an autoclave and the printed parts have demonstrated successful biocompatibility in tests of cytotoxicity (ISO 10993-5:2009), sensitization (ISO 10993- 10:2021) and irritation (ISO 10993-23:2021). The spring of required specification was wound with stainless steel. Alternatively, this dispenser system may contain a spring made of the shape memory material thereby eliminating the need for a shape memory stopper system.

Figure 9A shows the use of an AM to create a pattern with the bioink. In one embodiment, the barrel contents may be discharged using the shape memory trigger at one deposition site and the AM setup may be moved in programmed tool paths which results in smearing of the extruded the bioink by the EM in a pattern similar to the AM trajectory. A faithful reproduction of the AM trajectory may be achieved through repetitive strokes if necessary. Alternatively, the bioink may be discharged at a constant rate and then dragged along in a set pattern with the AM which may eliminate the need for repetitive strokes. The bioink material in many cases may require crosslinking for gelation of the printed pattern. This can be facilitated by exposing the print to a crosslinking agent which may be introduced through oral/orogastric gavage, or in some instances, a secondary intracorporeal robot may be employed to dispense the crosslinking agent precisely at the site. In cases where UV crosslinking may be required, a secondary crosslinking bot containing a UV LED, or the primary bot itself equipped with an SMD UV-LED and a micro silver oxide battery such as Seiko Instruments Inc., SR416SW, may be utilized. Alternatively, by utilizing biomaterials that naturally undergo a sol-gel transition over time or in response to temperature changes, the need for a secondary crosslinking step can be circumvented. Figure 8B shows the AM-EM configuration and a spiral pattern of an alginate ink printed using the mentioned strategy.

Figure 10A shows the AM-EM configuration wherein the intracorporeal robot is situated within an inverted T-25 Flask. The material within the barrel could be substituted with a bioink material containing cells at predetermined concentrations. Specifically in this illustration, the intracorporeal robot houses an alginate bioink blended with Human gastric fibroblasts at a density of 1 million cells/ml. Figure 10 B illustrates the bioprinted square pattern submerged in DMEM media. Subsequently, Figure 10 C demonstrates the presence of viable cells, as evidenced by Calcein-AM staining. Notably, cell viability within the printed structure was sustained for more than 16 days. A printed structure containing cells may aid in tissue regeneration through various mechanisms: integration into the lesion on top of which it was printed, serving as an in-situ bioreactor to produce therapeutics such as growth factors crucial for regeneration, or by functioning as a cell reservoir, providing cells through leaching behavior to support the healing process of the underlying lesion. Notably, leaching behaviour was observed within the T-25 flask and the leached cells proliferated as time progressed in this demonstration.

Figure 11 shows exemplars of how the dispense timing and velocity may be controlled. If the spring rate is not controlled pneumatically or through friction, the plunger extrudes the chamber contents rapidly resulting in a lump of bioink. This modality may be useful in some applications. For applications that require steady deposition of bioink or decreased ejection velocity, the spring rate may be controlled using the friction offered by the bore to piston diameter tolerance. By using a bore diameter gradient in the chamber, it is possible to achieve spring expansion in a controlled manner.

Alternatively, pneumatic dampening may also be implemented by tuning the material properties of the chamber contents. For example, by using a shear thickening bioinks or by tuning the rheological properties of the existing bioink such as viscosity, yield stress, time dependence etc., or by tuning the diameter of the extrusion nozzle. In the current invention, pneumatic dampening to decrease ejection velocity by ~3.5x was achieved using a combination of low nozzle diameter and high viscosity alginate bioink.

Figure 12 shows an embodiment of the present invention disclosing how a dispenser may be used to enable repairing of a haemorrhage site in a tissue wall. By depositing a hemostatic material over the site, hemostasis can be achieved. Chitosan-based hemostatic agents, Gelatin sponges, Oxidized cellulose, Kaolin-based dressings, Fibrin sealants, Microfibrillar collagen, Calcium alginate dressings, Thrombin-based hemostatic agents, Zeolite-based dressings, QuikClot and Alginate. By adjusting the AM-EM distance the normal force applied to the hemorrhage site can be tuned, which by itself or in conjunction with the discharged sealant material may help in hemostasis.

Figure 13 illustrates a intracorporeal robot-aspirator embodiment designed for collecting liquid biopsies or materials of interest from physiological environments. Liquid biopsies are crucial for diagnosing and tracking gastrointestinal (GI) diseases, including cancer, by detecting biomarkers and genetic material shed from GI tumors into gastric fluids. The previous material dispensing embodiment of the intracorporeal robot employed a spring compression-to-expansion mode for delivering biomaterials. Reversing this mechanism to enable expansion-to-compression by utilizing a spring expanded past its free length and locked in place with a stopper could enable the intracorporeal robot platform to retrieve liquid biopsies when the shape memory trigger is deployed. Consequently, the spring will compress and attain its free length, pulling the plunger and aspirating the liquid in the surrounding region. Alternatively, the stopper mechanism may also be replaced with a shape memory spring programmed to compress under external stimulus. This strategy ensures precision and minimally invasive sampling to improve diagnostic accuracy. In contrast, stool samples may only offer insights into the lower GI tract, lacking specificity for site-specific conditions.

In various embodiments disclosed herein, it is acknowledged that in scenarios where the penetration depth of Near-Infrared (NIR) radiation is inadequate to achieve intended objectives, a combination of trigger strategies or alternative trigger strategies may be utilized. For instance, consideration may be given to employing a HIFU (High Intensity focused Ultrasound) transducer positioned externally to the body to deliver heat energy to the intracorporeal robot site, thereby triggering the shape memory. In situations permitting multiple triggers, an NIR light source, such as an SMD LED or a laser diode sized to fit within the device footprint, may be seamlessly integrated into the intracorporeal robotic structure. This light source can be powered by a piezo harvester element, capable of converting externally applied ultrasound into electricity to energize the light source. Alternatively, the harvester may be replaced with a micro power source, such as a micro-silver oxide battery. A closed circuit may be achieved by controlling the gate voltage in a straightforward transistor or thyristor switch circuit. The gate voltage of the switch circuit can be controlled by a piezo element responsive to externally applied ultrasound. These methodologies present several but not limiting approaches through which surgical or printing objectives can be realized at tissue depths beyond the NIR reach in the above-mentioned embodiments.

All the embodiments mentioned herein may incorporate existing real-time imaging modalities to ensure precise deployment or accurate deposition of biological materials required in fulfilling the intracorporeal objectives. The microbot may be equipped with appropriate contrast agents to facilitate imaging via X- ray fluoroscopy or ultrasound imaging systems or a combination of both, allowing surgeons to monitor the printing process continuously. By integrating these imaging technologies directly into the intracorporeal robot’s design, feedback on tissue morphology, blood flow, and the positioning of the printing nozzle can be obtained in real-time. This capability enhances the surgeon's ability to navigate complex anatomical structures and adjust printing parameters on the fly, optimizing the outcome. Additionally, visualization may also be provided by endoscopy to further enhance the surgeon's understanding of the local environment and ensure precise placement of the printed materials.

One of skill will recognize that the present invention is not limited to the various embodiments and examplars above. As examples of other embodiments that fall within the scope of this invention, one of skill will recognize that while the exemples and embodiments above make use of a near-infrared optical trigger, it is also possible to achieve this triggering using other energetic trigger mechanisms, such as heat, ultrasonic excitation, and other such trigger mechanisms as would be apparent to one of appropriate skill.

Aspects and features of the invention thus concern a device for performing intracorporeal medical procedures comprising a magnet for steering using an applied magnetic field external to the body and a mechanically deformable structure including shape memory material that deforms upon application of a trigger stimulus that is provided external to the body.

In one medical application of the invention, the device can be tetherlessly actuated to an aneurysm site through external magnetic, optical or acoustic fields in its shape memory programmed state to assume a smaller footprint to promote easy endovascular navigation. The mechanically deformable structure may be an occlusion structure to at least partially occlude an aneurysm by at least partially isolating the aneurysm sac from the parent artery.

The occlusion structure may comprise a spring body with petaloid arms on both ends to obstruct blood flow at the aneurysm neck and stabilize the structure against the blood flow by exerting a counter force.

The spring body may comprise single or multiple or a combination of helical, serpentine, wave spring or other compress-uncompress programmable spring-like design forms.

The device may further comprise therapeutic agents incorporated in the intracorporeal robot to enhance the thrombus reorganization into a mature thrombus which in turn decreases the chances of embolization.

The therapeutic agents may be thrombus organization promoters or of hemostatic nature and may be discharged or exposed to the intra-aneurysmal environment from the decompression of the telescopic microcapsule during the shape recovery process.

The therapeutic agent may be impregnated in the shape memory material or located inside the spring body.

The device may further comprise a shape memory coil which in its programmed state remains wound over a carrier actuatable with external magnetic, optical, or acoustic fields.

Upon shape recovery, the wound coil may recover inside the aneurysm sac resulting in occlusion.

The device may further comprise therapeutic agents incorporated or intertwined into the coil to induce and enhance the thrombus reorganization.

The may further comprise a shape memory foam impregnated into the foam to assume a sac occlusive configuration and to induce thrombus formation and reorganization.

The device may include a shape memory trigger stimulus selected from temperature, light, pH, moisture, or magnetic fields.

The device may include a mechanically deformable structure includine a spring that drives ejection of a material from a chamber. The chamber may be sized so as to maintain a substantially constant material ejection velocity over a period of time of ejection.

In one medical application, the chamber may contain a bioink.

The device can be tetherlessly driven to spread the bioink over a wound site.

One of the medical applications concerns a method for performing aneurysm repair, comprising: applying an external magnetic field outside the body of a patient to magnetically steer a magnetcontaining device to the site of an aneurysm, and applying an external actuation to cause a shape deformation in the shape memory material to at least partially occlude the aneurysm sac from the parent artery.

The method may further include inducing thrombus formation within the aneurysm.

The external shape memory actuation may be based on a stimulus of temperature, light, pH, moisture, or a magnetic field.

One of the medical applications concerns a method for repairing a hemorrhage site in a tissue or organ wall, comprising: applying an external magnetic field outside the body of a patient to magnetically steer a magnetcontaining device to the site of a hemorrhage, and applying an external trigger to cause a shape deformation in a shape memory material to eject bioink onto the site of the hemorrhage to at least partially seal said hemorrhage.

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List of features referenced

Remotely controllable in vivo robot system 100

Extracorporeal actuator system 102

Robot arm 103

Actuating magnet (AM) 104

Shape memory actuator 105

Near Infra red (NIR) source

Intracorporeal robot 1

Effector magnet (EM) 2

Medical device 3

Occlusion structure 3 a

Dispensing device 3b Drug delivery device 3 c Sample collection device 3d Surgical tool 3e

Shape memory structure 4

Trigger mechanism 5

Filament / wire structure 6

Coil

Filament bundle

Petaloid structure 7

Spring mechanism 9

Payload 10

Carrier / support structure Spring 14

Container 16

Plunger 18 Inlet 20

Active substance 22

Drug

Claims

1. An intracorporeal robot (1) for deployment in a body tract, comprising: a permanent magnet constituting an effector magnet (2) configured to be guided by an extracorporeal actuating magnet (104), and a medical device (3) coupled to the effector magnet, the medical device comprising a shape memory structure (4), configured for tetherless actuation by an extracorporeal shape memory actuator (105), wherein the shape memory structure (4) comprises a trigger mechanism (5) and the medical device comprises a payload (10) including a container (16) with a plunger (18) or flexible wall, and a spring (9, 14) applying pressure on the plunger or flexible wall, wherein the trigger mechanism (5) is configured to block movement of the spring, the trigger mechanism being releasable upon shape memory actuation to allow the spring to displace the plunger or flexible wall of the container.

2. The intracorporeal robot of the preceding claim wherein the trigger mechanism comprises a restraining element, for instance a transverse beam or a circlip.

3. The intracorporeal robot of any preceding claim wherein the medical device comprises an active therapeutic substance (22).

4. The intracorporeal robot of the preceding claim wherein the active substance is contained in the container (16) of the medical device, the container configured for actuation from a closed configuration to an open configuration by actuation of the shape memory structure.

5. The intracorporeal robot of the preceding claim wherein the spring is configured for applying a positive pressure on the active substance contained in the container upon shape memory actuation of the medical device, for dispensing the therapeutic substance out of the container.

6. The intracorporeal robot of any preceding claim wherein the container comprises an internal bore with a diameter gradient configured to control a spring rate of the spring.

7. The intracorporeal robot of any one of claims 3 to 6 wherein the medical device is configured for drug delivery in a body tract, for instance for dispensing the active substance on a wall of a body tract, for instance a hemostatic agent in gastrointestinal medical applications.

8. The intracorporeal robot of any of claims 1 or 2 wherein the medical device is a sample collection device (3d) and the spring applies a negative pressure on the plunger or flexible wall of the container configured to generate a negative pressure within the container to draw in liquid into the container upon shape memory actuation of the medical device.

9. The intracorporeal robot of any preceding claim wherein the shape memory structure comprises or consists of a bioresorbable polymer, wherein the bioresorbable polymer may be selected from a group consisting of polylactic acid (PLA), polyurethane (PU), poly(s- caprolactone) (PCL), polydioxanone (PDO), and copolymers thereof, and wherein the polymer may be doped with melanin in a volume percentage range between 1 and 12%, preferably between 4 and 12%.

10. The intracorporeal robot of any preceding claim wherein the shape memory structure is configured for electromagnetic actuation, preferably by radiation in a near infra-red range having a wavelength range from 760 nm to 1500 nm.

11. A remotely controllable in vivo robot system (100) comprising the intracorporeal robot (1) according to any one of claims 1 to 10, and an extracorporeal actuator system (102) including an actuating magnet (104) and a shape memory actuator (105).

12. The system according to the preceding claim wherein the extracorporeal actuator system (102) comprises a multi-axis robot arm (103), the actuating magnet (104) mounted on the multiaxis robot arm, wherein the actuating magnet may comprise a permanent magnet displaceable around a patient support table by the robot arm.

13. The system according to any one of the two directly preceding claims wherein the shape memory actuator (105) comprises a near infra-red source.

14. The system according to any one of the three directly preceding claims wherein the system is configured for extruding a therapeutic material by guiding the intracorporeal robot in a body tract and actuating the shape memory structure by activation of the shape memory actuator and steering the intracorporeal robot such through predetermined paths such that the therapeutic material is deposited in accordance with the predetermined paths.

15. The system according to any one of claims 11 to 13 wherein the system is configured for biopsy collection by guiding the intracorporeal robot in a body tract and actuating the shape memory structure by activation of the shape memory actuator.

16. An intracorporeal robot (1) for deployment in a body tract, comprising: a permanent magnet constituting an effector magnet (2) configured to be guided by an extracorporeal actuating magnet (104), and a medical device (3) coupled to the effector magnet, the medical device comprising a shape memory structure (4) configured for tetherless actuation by an extracorporeal shape memory actuator (105), wherein the shape memory structure (4) comprises a wire structure (6) or a petaloid structure (7), wherein the shape memory structure has a shape with an outer envelope having a first volume prior to shape memory actuation and a second volume after shape memory actuation, the second volume being greater than the first volume such that the shape memory structure is configured to form an occlusion structure (3a) upon shape memory actuation.

17. The intracorporeal robot of claim 16 wherein the wire structure is configured to transform into a filament bundle upon shape memory actuation.

18. The intracorporeal robot of claim 16 wherein the petaloid structure comprises a spring body (9) with petaloid arms on both ends.

19. The intracorporeal robot of the preceding claim wherein the spring body may comprise single or multiple or a combination of helical, serpentine, wave spring or compress-uncompress programmable spring-like design forms.

20. The intracorporeal robot of any one of claims 16 to 19 wherein the medical device comprises an active therapeutic substance (22).

21. The intracorporeal robot of the preceding claim, wherein the active substance is coated on the shape memory structure.

22. The intracorporeal robot of claim 20, wherein the active substance is contained in a container (16) of the medical device, the container configured for actuation from a closed configuration to an open configuration by actuation of the shape memory structure.

23. The intracorporeal robot of any one of claims 16 to 22 wherein the medical device comprises a payload (10) coupled to the shape memory structure, the payload (10) comprising any one or more of: a drug delivery device (3c), a sample collection device (3d), a bioink dispensing device (3b) or a surgical tool (3e).

24. The intracorporeal robot of any one of claims 16 to 23 wherein the medical device comprises a payload (10) including a container (16) with a plunger (18) or flexible wall, and a spring (9, 14) applying pressure on the plunger or flexible wall, optionally wherein:

- the container comprises a therapeutic substance and the spring is configured for applying a positive pressure on the active substance contained in the container upon shape memory actuation of the medical device, for dispensing the therapeutic substance out of the container, or

- the medical device is a sample collection device (3d) and the spring applies a negative pressure on the plunger or flexible wall of the container configured to generate a negative pressure within the container to draw in liquid into the container upon shape memory actuation of the medical device

25. The intracorporeal robot of either of the preceding claim wherein the shape memory structure comprises a trigger mechanism (5) blocking movement of the spring, the trigger mechanism being releasable upon shape memory actuation to allow the spring to displace the plunger or flexible wall of the container.

26. The intracorporeal robot of any one of claims 16 to 25 wherein the shape memory structure comprises or consists of a bioresorbable polymer, wherein the bioresorbable polymer may be selected from a group consisting of polylactic acid (PLA), polyurethane (PU), poly(s- caprolactone) (PCL), polydioxanone (PDO), and copolymers thereof, and wherein the polymer may be doped with melanin in a volume percentage range between 1 and 12%, preferably between 4 and 12%.

27. The intracorporeal robot of any one of claims 16 to 26 wherein the shape memory structure is configured for electromagnetic actuation, preferably by radiation in a near infra-red range having a wavelength range from 760 nm to 1500 nm.

28. The intracorporeal robot of any one of claims 16 to 27 wherein the medical device is configured for drug delivery in a body tract, for instance for dispensing an active substance on a wall of a body tract, for instance a hemostatic agent in gastrointestinal medical applications.

29. A remotely controllable in vivo robot system (100) comprising the intracorporeal robot (1) of any preceding claim, and an extracorporeal actuator system (102) including an actuating magnet (104) and a shape memory actuator (105).

30. The system according to the preceding claim wherein the extracorporeal actuator system (102) comprises a multi-axis robot arm (103), the actuating magnet (104) mounted on the multiaxis robot arm, wherein the actuating magnet may comprise a permanent magnet displaceable around a patient support table by the robot arm.

31. The system according to any one of the two directly preceding claims wherein the shape memory actuator (105) comprises a near infra-red source.

32. The system according to any one of the three directly preceding claims wherein the system is configured for occlusion of an aneurysm sack by guiding the intracorporeal robot in a body tract into the aneurism sack and actuating the shape memory structure by activation of the shape memory actuator (105).

33. A method for repairing a hemorrhage site in a tissue or organ, the method comprising: providing a remotely controllable in vivo robot system (100) comprising an intracorporeal robot (1) and an extracorporeal actuator system (102) including an actuating magnet (104) and a shape memory actuator (105), wherein the intracorporeal robot comprises a permanent magnet constituting an effector magnet (2) configured to be guided by the actuating magnet (104), and a medical device (3) coupled to the effector magnet, the medical device comprising a shape memory structure (4), configured for tetherless actuation by the shape memory actuator, wherein the shape memory structure (4) comprises a trigger mechanism (5) and the medical device comprises a payload (10) including a container (16) with a plunger (18) or flexible wall, and a spring (9, 14) applying pressure on the plunger or flexible wall, wherein the trigger mechanism (5) is configured to block movement of the spring, the trigger mechanism being releasable upon shape memory actuation to allow the spring to displace the plunger or flexible wall of the container; injecting the intracorporeal robot into a body of a patient, preferably orally; applying an external magnetic field outside the body of the patient using the actuating magnet to magnetically guide the effector magnet of the intracorporeal robot in a body track of the patient to the site of the hemorrhage; and applying an external trigger using the shape memory actuator configured to cause a shape deformation in the shape memory structure such that the trigger mechanism is released to unblock the movement of the spring, wherein an active therapeutic substance is extruded out of the container onto the site of the hemorrhage upon the shape deformation to at least partially seal said hemorrhage.

34. The method according to the preceding claim, the method further comprising steering the effector magnet using the actuating magnet through predetermined path such that the active therapeutic substance is deposited in accordance with the predetermined path.

35. The method according to any one of the two directly preceding claims wherein the extracorporeal actuator system comprises a multi-axis robot arm (103), the actuating magnet mounted on the multi-axis robot arm, wherein the actuating magnet may comprise a permanent magnet displaceable around a patient support table by the robot arm.

36. The method according to any one of the three directly preceding claims wherein the shape memory actuator (105) comprises a near infra-red source.

37. The method according to any one of the four directly preceding claims wherein the container comprises an internal bore with a diameter gradient configured to control a spring rate of the spring.

38. The method according to any one of the five directly preceding claims wherein the shape memory structure comprises or consists of a bioresorbable polymer, wherein the bioresorbable polymer may be selected from a group consisting of polylactic acid (PLA), polyurethane (PU), poly(s-caprolactone) (PCL), polydioxanone (PDO), and copolymers thereof, and wherein the polymer may be doped with melanin in a volume percentage range between 1 and 12%, preferably between 4 and 12%.