System and method for in-VIVO tissue strengthening to enhance surgical outcomes

Abstract

The present disclosure provides systems and methods for in-vivo tissue strengthening. The method includes applying a photosensitive dye to in-vivo tissue at a surgical location and exposing the tissue to light at a wavelength corresponding to an absorption spectrum of the photosensitive dye to initiate photochemical cross-linking in the tissue at the surgical location.

Description

SYSTEM AND METHOD FOR IN-VIVO TISSUE STRENGTHENING TO ENHANCE SURGICAL OUTCOMES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on, claims priority to, and incorporates herein by reference US Provisional Application Serial No. 63 / 774,920, filed March 20, 2025.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] N / ABACKGROUND

[0003] The present disclosure relates generally to systems and methods for in-vivo treatment of tissue to enhance tissue strength, particularly in the context of surgical procedures involving suturing, cuffs, stables, or other fixation devices. More specifically, the invention pertains to techniques for strengthening tissue before, during, or after suturing or other surgical interventions or fixing by utilizing photochemical cross-linking induced by photosensitive dyes.

[0004] Suturing is a fundamental technique in surgical procedures, used to approximate and secure tissue. While sutures themselves rarely fail, the tissue holding the sutures can often be the weak point, leading to fixation failure. This issue is particularly prevalent in certain types of surgeries, such as orthopedic procedures like shoulder repairs, or neurosurgical operations involving the dura mater.

[0005] Traditional approaches to tissue repair have primarily focused on improving suturing techniques or developing stronger suture materials. However, these methods do not address the underlying issue of tissue weakness. There remains a need for innovative approaches that can overcome these shortcomings and improve the overall success rate of surgical procedures.SUMMARY

[0006] The present disclosure overcomes the drawbacks by providing systems and methods for in-situ strengthening of tissue. Systems and methods are provided to strengthening tissue before, during, or after suturing or other surgical intervention or fixingby utilizing photochemical cross-linking induced by photosensitive dyes and light.

[0007] In accordance with one aspect of the present disclosure, a system is provided for in-vivo tissue strengthening. The system includes a reservoir configured to hold a photosensitive dye, an excitation source, and a pump configured to deliver the photosensitive dye to a surgical location. The system also includes a control system configured to control operation of at least one of the excitation source and the pump to control one of delivery of the photosensitive dye or operation of the excitation source to safely deliver the photosensitive dye to in-vivo tissue at the surgical location or safely deliver light at a wavelength corresponding to an absorption spectrum of the photosensitive dye to initiate photochemical cross-linking in the in-vivo tissue at the surgical location.

[0008] In accordance with another aspect of the present disclosure, a method is provided for in-vivo tissue strengthening. The method includes applying a photosensitive dye to in-vivo tissue at a surgical location, and exposing the tissue to light at a wavelength corresponding to an absorption spectrum of the photosensitive dye to initiate photochemical cross-linking in the tissue at the surgical location.

[0009] In accordance with yet another aspect of the present disclosure, a kit is provided for in-vivo tissue strengthening. The kit includes a photosensitive dye, a photoactivator system comprising an excitation source configured to emit light at a wavelength corresponding to an absorption spectrum of the photosensitive dye, and a controller configured to control the excitation source to safely deliver the photosensitive dye to in-vivo tissue a surgical location.

[0010] The above are non-limiting examples. Other features and aspects are described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Fig. 1 is a schematic diagram of a system for in-vivo tissue strengthening in accordance with the present disclosure.

[0012] Fig. 2 is a flow chart setting forth some non-limiting, example steps for a process in accordance with the present disclosure.

[0013] Fig. 3A is a graphic illustration of a plication procedure.

[0014] Fig. 3B is a set of graphs showing the substantial advancement of subjects of aplication procedure in accordance with the systems and methods of the present disclosure over those without the systems and methods provided herein.

[0015] Fig. 4 is a graph showing distinct differences between treated and control samples subjected to gap testing.DETAILED DESCRIPTION

[0016] The present disclosure relates to an in-vivo and in-situ tissue strengthening system designed for use during surgical procedures. Referring to Fig. 1, a system 100 is provided that may include a reservoir 102 and a photoactivator system 104. The system 100 may be used in conjunction with surgical resources 106 to perform a process, as will be described, on a patient 108.

[0017] The reservoir 102 may be a reservoir of a photosensitive dye. As illustrated, the reservoir 102 may be separate from the photoactivator system 104, or may be integrated therewith. The reservoir 102 may be configured to deliver the photosensitive dye to the patient 108. In this way, the reservoir 102 may be configured to coordinate with the photoactivator system 104, or may operate independently. The reservoir may include a pump 110. Alternatively, the pump 110 may be arranged in the photoactive system 104 to draw photosensitive dye from the reservoir 110. In either case, the system 100 is configured to deliver photosensitive dye to an in-vivo, in-situ surgical location 112 in the patient 108. The surgical location 112 may include a tissue interface, such as a fixation device, such as a suture, staple, cuff, or other fixation device may be deployed to the surgical location 112 to fix the tissue interface. Other fixation devices may include, for example, suture anchors, interference screws, cortical fixation devices, nails, and the like. In some cases, the fixation device may include sutures arranged in various configurations, such as a modified Kessler suture technique, Krackow suture, Bunnell suture, Mason-Allen technique, U-suture configurations, Running or interrupted sutures. For example, in some plication procedures, a series of interrupted sutures, such as five interrupted sutures, may be used to secure the tissue. The sutures may be formed from various materials. Some non-limiting examples include Vicryl, monociyl, PDSII, Chromic / plain gut, prolene, ethilon, silk, ethibond, barbed sutures, stainless steel wires, and the like In one, specific, non-limiting example, the suture may be a high-strength, multi-strand, ultra-high molecular weight polyethylene (UHMWPE)core surgical suture, with or without a braided polyester jackets, such as FiberWire (e.g., 4-0 FiberWire) or other suitable suture materials. FiberWire® is a registered trademark of Arthrex, Inc. As will be described, the surgical location 112 may be accessible directly, such as through a surgical opening providing direct access to the surgical location 112, or a scope 114 or other minimally invasive device may be used to access the surgical location 112. In either case, the system 110 is configured to provide in-vivo and in-situ tissue strengthening.

[0018] The system 100 also includes the photoactivator system 104, which includes an excitation source 116, and a control system 118. The excitation source 116 can include one or more light- emitting arrangements that include optics to uniformly and controllably irradiating the surface of the surgical location with light having a particular fluence and one or more particular wavelengths, when the photoactive dye is delivered. The excitation source 116 can include light-emitting diodes (LEDs), laser diodes, or the like. The number and / or shape of the excitation source 116 (including the associated optics) can be selected to provide a desired fluence at the surgical location 112. In one non-limiting example, the light can be delivered at a fluence of between 80-120 J / cm2or an irradiance between 01.-1.5 W / cm2or other values or parameters selected based on the dye chosen and / or the tissue. In some configurations, the excitation source 116 can include reflectors, diffusers, waveguides, or other optical components to improve or direct light to the surgical location 112. In an open surgical location 112, the optics may be configured to uniformly deliver the light to the surgical location 112. On the other hand, when using a scope 114, the optics may be configured to direct light into the scope 114.

[0019] The photoactivator system 104 also includes the control system 118. The control system can be used to control the operation of the excitation source 116 and / or the pump 110 of the reservoir 102. More particularly, the control system 118 can control aspects of the excitation source 116 including fluence, wavelength, or other excitation properties. Also, the control system 118 may be configured to receive feedback from the surgical location 112 to effectuate a close-loop control. In this way, the photoactivator system 104 may include a user interface 120 through which users, such as surgeons or other clinicians may select operational parameters, as will be described.

[0020] As described, the reservoir 102 is configured to hold a photosensitive dye122. The photosensitive dye 122 may be a compound capable of initiating photochemical cross-linking when exposed to light of a preselected wavelength. Some non-limiting examples of wavelengths may include 400 nm to about 700 nm, or about 532 nm, but other wavelengths may be selected based on the dye chose and / or the tissue. The photosensitive dye 122 may be selected based on its ability to interact with collagen molecules in the tissue and form covalent bonds upon light activation.

[0021] Thus, the excitation source 116 may be configured to emit light at a specific wavelength or range of wavelengths that correspond to the absorption spectrum of the chosen photosensitive dye 122. In some cases, the excitation source 116 may be adjustable to allow for varying intensity and exposure times depending on the specific tissue being treated and the desired degree of strengthening, and maybe controlled by the control system 118 and / or using the user interface 120.

[0022] The in-vivo tissue strengthening system 100 may be utilized intraoperatively, allowing surgeons to apply the photosensitive dye 112 directly to weakened or fragile tissue exposed during surgery. That is, in the case of an open surgical location 112, one or more applicators 124 may be used to ensure a precise and controlled delivery of the photosensitive dye 122 to the surgical location 112 during a surgical procedure. These applicators 124 may take various forms depending on the specific surgical application and the accessibility of the tissue to be treated.

[0023] In some non-limiting examples, the applicator 124 may include flexible fiber optic cables that allow for the delivery of light to the surgical location 124. These fiber optic cables may be designed to be thin and maneuverable, allowing surgeons to direct the light precisely where it is needed without obstructing their view or interfering with other surgical instruments. The applicator 124 may also incorporate safety features to protect both the patient and the surgical team. In some cases, these safety features may include automatic shut-off mechanisms communicating with the control system 118 to prevent overexposure, as well as filters to block potentially harmful wavelengths of light.

[0024] Following application of the photosensitive dye 122, the tissue a the surgical location 112 may be exposed to light from the excitation source 116, initiating the photochemical cross-linking process. Additionally or alternatively, the in-vivo tissue strengthening system 100 may be utilized intraoperatively, during minimally-invasivesurgical procedures, allowing surgeons to apply the photosensitive dye 112 directly to tissue via a scope 114 or other surgical tool 126. In this way, the photosensitive dye 122 may be delivered through the scope 114 or other surgical tool 126 to deliver the photosensitive dye 122 to the surgical location 112.

[0025] Regardless of the particulars of the surgical procedure, the system 100 may be used to reinforce tissue in surgical locations 112 where sutures or other fixation devices or systems 128 are to be or have been placed. By strengthening the tissue around a surgical location 112 and, more particularly, a fixation site, the system can reduce the risk of tissue tearing or suture pull-through during and after surgical procedures. The in-vivo nature of this system 100 allows for strengthening of tissue during surgical procedure, thereby improving surgical outcomes and reducing the risk of post-operative complications related to tissue weakness or failure.

[0026] In some cases, the photosensitive dye 122 used for in-vivo tissue strengthening may be Rose Bengal. Rose Bengal is a xanthene dye that has been shown to be effective in ex-vivo photochemical cross-linking applications. Other photosensitive dyes are also contemplated, such as toluidine blue, riboflavin, Genipin, or EDC. In particular, the composition of the photosensitive dye may be adapted for in-vivo use to ensure biocompatibility and safety in living tissue. In some cases, the Rose Bengal may be formulated in a sterile, isotonic solution suitable for application to surgical sites. The concentration of Rose Bengal in the solution may be adjusted to optimize its effectiveness while minimizing potential toxicity.

[0027] To enhance biocompatibility, the photosensitive dye 122 composition may include additional components. In some cases, a biocompatible carrier may be used to facilitate even distribution of the dye across the target tissue. This carrier may be a hydrogel or other biocompatible polymer that allows for controlled release of the photosensitive dye 122.

[0028] The pH of the photosensitive dye 122 composition may be adjusted to match physiological conditions. In some cases, a processing system 130 may be incorporated to maintain the pH within a range that is both effective for photochemical cross-linking and safe for living tissue. Other processing may include heating or other chemical treating or balancing. As non-limiting examples, the photosensitive dye 122 may include antioxidantsor free radical scavengers. These components may help mitigate potential oxidative stress on surrounding healthy tissue during the photochemical cross-linking process. In some cases, the photosensitive dye 122 may be modified to improve its tissue penetration properties. This may involve the use of penetration enhancers or the encapsulation of photosensitive dye 122 in nanoparticles designed for improved tissue uptake. The stability of the photosensitive dye 122 for in-vivo use may be enhanced through the addition of preservatives or stabilizers. These additives may help maintain the efficacy of the photosensitive dye 122 over time and during storage, while still being compatible with living tissue. In some cases, the photosensitive dye 122 may be formulated as a two-part system, where the photosensitive dye 122 and a catalyst or activator 132 are kept separate until just before application. This approach may help preserve the reactivity of the components and allow for precise control over the initiation of the photochemical cross-linking process.

[0029] In some cases, the system 100 may be configured as a kit that may include, for example, the photoactivator system 104 and reservoir 102. Additionally, in some configurations, the photosensitive dye 122 and, optionally, any activator 132 may be included in the kit.

[0030] The excitation source 116 is designed to activate the photosensitive dye 122. Thus, the excitation source 116 may emit light at a specific wavelength or range of wavelengths that correspond to the absorption spectrum of the chosen photosensitive dye 122. In some cases, green light may be used as the appropriate wavelength for photochemical cross-linking. The use of green light may be particularly effective when used in conjunction with certain photosensitive dyes, such as Rose Bengal.

[0031] The excitation source 116 may be adjustable or controlled by the control system 118 to allow for varying intensity and exposure times depending on the specific tissue being treated and the desired degree of strengthening. In some cases, the intensity of the light may be controlled by the excitation source 116 to optimize the cross-linking process while minimizing potential damage to surrounding tissues. For example, to ensure consistent and effective light delivery, the control system 118 may include a built-in timer and dosimeter. In some cases, these features may allow surgeons to precisely control the duration and intensity of light exposure, ensuring that the tissue receives the optimal amount of energy for effective cross-linking.

[0032] The system 100 may be specifically designed for use in a surgical setting, taking into account factors such as sterility and precision. In some cases, the excitation source 116 may be enclosed in a sterile, disposable sheath to maintain the sterile field during surgical procedures. The light delivery system may also incorporate features to ensure precise targeting of the light to the specific area of tissue that has been treated with the photosensitive dye 122.

[0033] The light source may be designed to be portable and easily integrated into existing surgical setups. In some cases, the light source may be mounted on a flexible arm that can be easily positioned and adjusted during surgery, allowing for hands-free operation once in place.

[0034] Additionally or alternatively, monitoring may include one or more sensors 132 to acquire data about other parameters and provide feedback to the processing system 130 and / or control system 118, and / or directly to a clinician, such as via the user interface 120. For example, the sesnsor(s) 132 may include temperature sensors or oxygen sensors. In one non-limiting example, a temperature sensor may, for example via non-contact temperature monitoring, provide feedback on tissue temperature or the surface temperature of the tissue. In another non-limiting example, the sensor(s) 132 may be configured to monitor oxygen or oxygen depletion. Thus, the processing system 130 and / or control system 118 may be configured to coordinate operation of the pump 110 to deliver the dye 112 and / or the excitation source 116 and activator 132 to maintain a desired oxygen level at the surgical location 112. Additionally or alternatively, a oxygen source 134 maybe included to maintain the oxygen available to the tissue at the surgical location 112. In a similar manner, a heater 136 may be included to maintain a desired temperature. Regardless of the particular sensor and / or other components available to or controlled by the processing system 130 and / or control system 118, the underlying system 100 may be configured to maintain a desired surgical environment.

[0035] Referring now to Fig. 2, some non-limiting example steps 200 in a process in accordance with the present disclosure are provided. The process may start in conjunction with a surgical procedure. Portions or all of the surgical procedure may be performed, such that the surgical site is ready to receive sutures or other fixation systems or devices, or may have just received sutures or other fixation systems. That is, the process described hereinmay be performed before, during, or after placement of sutures or other fixation systems.

[0036] The application method for in-vivo use of the tissue strengthening system may involve several preparation steps 202. For example, some steps may include performing some or all of a surgical procedure. Others may be performed to ensure safe and effective treatment before, during, or after surgical procedures. In some cases, the surgical site may be prepared. For example, the surgical site may be cooled or otherwise preconditioned. As another non-limiting example, the tissue or surgical site may be prepared by carefully exposing the target tissue and isolating it from surrounding healthy tissue. This isolation may help minimize unintended exposure of healthy tissue to the photosensitive dye and light.

[0037] As indicated at process block 202, the photosensitive dye is delivered to the surgical location. The photosensitive dye may be applied directly to the target tissue. This may be performed via direct, open access to the surgical location, or via a scope or other minimally-invasive surgical tool. Application may be achieved, optionally, using specialized applicators. These applicators may be designed to allow for precise and controlled delivery of the dye. In some cases, the applicators may take the form of fine-tipped brushes, sprayers, or sponges, depending on the specific tissue being treated and the accessibility of the surgical site.

[0038] To ensure even distribution of the dye across the target tissue, multiple application techniques may be employed. In some cases, gentle massaging or dabbing of the dye onto the tissue surface may be performed. In other cases, the dye may be applied in a thin, uniform layer using specially designed applicators.

[0039] The concentration and volume of the photosensitive dye applied may be carefully controlled to achieve optimal results while minimizing potential toxicity. In some cases, the dye may be diluted to a specific concentration based on the type and condition of the tissue being treated. Also, in some cases, the viscosity of the dye composition may be modified to suit different application scenarios. For procedures involving vertical or overhanging tissue surfaces, a more viscous formulation may be used to improve adherence and prevent runoff. For procedures requiring dye penetration into deeper tissue layers, a less viscous formulation may be preferred to facilitate diffusion.

[0040] After application of the dye, an optional waiting period may be observed atprocess block 206 to allow for adequate penetration into the tissue. The duration of this waiting period may vary depending on the specific dye used and the characteristics of the target tissue. Also at process block 206, further preparation may be performed before excitation of the dye. For example, excess dye may be removed from the tissue surface to prevent unintended cross-linking of surrounding tissues. In some cases, this removal may be accomplished using sterile saline rinses or gentle blotting with sterile gauze.

[0041] The light source may then be positioned to illuminate the treated area at process block 208. In some cases, specialized light guides or fiber optic cables may be used to direct the light precisely to the target tissue, minimizing exposure to surrounding areas. The duration and intensity of light exposure may be carefully controlled based on the specific tissue being treated and the desired degree of strengthening. In some cases, the light source may be equipped with a timer and intensity control to ensure consistent and appropriate dosing. During light exposure, protective measures may be taken to shield surrounding tissues from unintended light exposure. In some cases, this may involve the use of opaque drapes or specialized light-blocking instruments.

[0042] Following the light exposure period, at optional process block 210, post processing may be performed. For example, the treated tissue may be rinsed with sterile saline to remove any residual dye. In some cases, additional protective measures may be applied to the treated area, such as the application of a biocompatible barrier or sealant.

[0043] During surgical procedures, the photosensitive dye may be applied to the target tissue before, during, or after suture placement, depending on the specific requirements of the procedure. In this way, any of the foregoing steps may be repeated or may see iterative steps. In some cases, the dye may be applied to the tissue edges prior to suturing, allowing for strengthening of the tissue before it is approximated. Alternatively, the dye may be applied after suture placement to reinforce the sutured area and potentially reduce the risk of suture pull-through.

[0044] Throughout the application process, care may be taken to maintain sterility and minimize tissue trauma. In some cases, the entire procedure maybe performed under sterile conditions using aseptic techniques to reduce the risk of infection.

[0045] The application method may be adapted based on the specific surgical procedure and the anatomical location of the target tissue. In some cases, the method may be modifiedto accommodate minimally invasive surgical techniques or to treat tissues in hard-to-reach areas.

[0046] Monitoring of tissue response during and after the application process may be performed to ensure safety and efficacy. In some cases, this monitoring may involve visual inspection, tissue perfusion assessment, or the use of specialized imaging techniques. Additionally or alternatively, as discussed above, monitoring may include sensors to acquire data about other parameters and provide feedback to the controller or processor, and / or directly to a clinician.

[0047] The application method may also include steps to verify the effectiveness of the treatment. In some cases, this may involve gentle manipulation of the treated tissue to assess its mechanical properties or the use of intraoperative testing methods to evaluate tissue strength.

[0048] Notably, the photochemical cross-linking process for tissue strengthening in living tissue may involve several steps and mechanisms that contribute to the reinforcement of collagen and increased tissue strength. This process may differ in some aspects from ex-vivo applications due to the dynamic nature of living tissue. In some cases, the process may begin with the application of a photosensitive dye to the target tissue. The dye molecules may penetrate the tissue and associate with collagen fibers. When exposed to light of an appropriate wavelength, the dye molecules may become excited and enter a higher energy state. The excited dye molecules may then interact with nearby oxygen molecules, potentially generating reactive oxygen species (ROS). These ROS may include singlet oxygen or other free radicals. In some cases, the excited dye molecules may also directly interact with specific amino acids in the collagen molecules.

[0049] The generated ROS or the directly excited dye molecules may react with certain amino acid residues in the collagen molecules, such as histidine, tyrosine, or cysteine. This reaction may create reactive sites on the collagen molecules. In some cases, these reactive sites may be in the form of free radicals or other chemically active moieties. The reactive sites on different collagen molecules may then interact with each other, potentially forming covalent bonds between adjacent collagen molecules or between different regions of the same molecule. This cross-linking process may occur both within individual collagen fibers and between adjacent fibers. The formation of these additional covalent bonds may increasethe mechanical strength and stability of the collagen network. In some cases, this may result in improved tensile strength, reduced elasticity, and increased resistance to degradation of the treated tissue.

[0050] In living tissue, the photochemical cross-linking process may be influenced by various factors that are not present in ex-vivo applications. The presence of blood flow and interstitial fluids may affect the distribution and concentration of the photosensitive dye within the tissue. In some cases, this may result in a more heterogeneous distribution of cross-links compared to ex-vivo applications.

[0051] The metabolic activity of cells within living tissue may also impact the crosslinking process. In some cases, cellular antioxidant systems may partially counteract the effects of ROS generated during the photochemical reaction. This may potentially lead to a more gradual or controlled cross-linking process compared to ex-vivo applications.

[0052] The dynamic nature of living tissue may also influence the long-term outcomes of the cross-linking process. In some cases, the body's natural tissue remodeling processes may gradually modify the cross-linked collagen over time. This may result in a more dynamic and adaptive strengthening effect compared to the more static outcome typically observed in ex-vivo applications.

[0053] The presence of various enzymes and proteins in living tissue may also affect the reaction kinetics of the photochemical cross-linking process. In some cases, these biomolecules may compete with collagen for interactions with the excited dye molecules or ROS, potentially altering the efficiency or specificity of the cross-linking reaction.

[0054] The pH and ionic environment within living tissue may differ from those typically used in ex-vivo applications. In some cases, these differences may influence the reactivity of the photosensitive dye or the stability of the formed cross-links. This may necessitate adjustments to the dye formulation or light exposure parameters to achieve optimal results in vivo.

[0055] The three-dimensional structure and organization of collagen fibers in living tissue may also impact the cross-linking process. In some cases, the natural alignment and spacing of collagen molecules in intact tissue may affect the distribution and density of formed cross-links, potentially leading to different mechanical outcomes compared to ex-vivo applications using isolated or processed collagen.

[0056] The presence of other extracellular matrix components in living tissue, such as proteoglycans and elastin, may also influence the photochemical cross-linking process. In some cases, these components may interact with the photosensitive dye or participate in secondary reactions, potentially modifying the overall tissue strengthening effect.

[0057] The ongoing cellular processes in living tissue, including collagen synthesis and degradation, may interact with the photochemical cross-linking process. In some cases, this may result in a more complex and dynamic strengthening effect that evolves over time, as opposed to the more immediate and static outcome typically observed in ex-vivo applications.

[0058] The in-vivo tissue strengthening system may be applied in various surgical procedures to enhance tissue repair and improve outcomes. In some cases, the system may be utilized in pericardial repair procedures. During cardiac surgery, the pericardium may be opened to access the heart. After the primary procedure, the photosensitive dye may be applied to the edges of the pericardial incision. The treated area may then be exposed to light of the appropriate wavelength to initiate photochemical cross-linking. This process may strengthen the pericardial tissue, potentially reducing the risk of post-operative complications such as pericardial effusion or adhesions.

[0059] In some cases, the system may be employed in colon repair procedures. During colorectal surgery, if a perforation or weak area in the colon wall is identified, the photosensitive dye may be applied to the affected area. After light exposure and crosslinking, the strengthened tissue may provide a more robust foundation for sutures or staples, potentially decreasing the risk of anastomotic leaks.

[0060] The in-vivo tissue strengthening system may also be applied in tendon repair procedures, particularly for rotator cuff and Achilles tendon injuries. In rotator cuff repair, the photosensitive dye may be applied to the torn tendon edges and the bone attachment site. After light-induced cross-linking, the strengthened tendon tissue may better withstand the forces applied during and after surgical reattachment, potentially reducing the risk of retear. Similarly, in Achilles tendon repair, the system may be used to reinforce the tendon at the repair site, potentially improving the mechanical properties of the healed tissue. In some cases, tendon repairs may utilize specific suture techniques to secure the tendon ends, such as a modified Kessler suture technique or U-suture configurations. The modified Kesslersuture may be particularly suitable for flexor tendon repairs, where the suture passes through the core of the tendon substance on either side of the transection site to provide secure approximation of the tendon ends. U-suture configurations may be used in loadbearing applications to distribute forces across the tissue. The sutures may be formed from various materials, such as high-strength, multi-strand, ultra-high molecular weight polyethylene (UHMWPE) core surgical sutures with or without a braided polyester jackets, such as FiberWire or other suitable suture materials. FiberWire® is a registered trademark of Arthrex, Inc. By applying the photosensitive dye and initiating photochemical crosslinking before or after suture placement, the tissue surrounding the sutures may be strengthened, potentially reducing gap formation during cyclic loading and improving repair stability.

[0061] In some cases, the system may be utilized to address visceral leaks. For instance, in procedures involving the gastrointestinal tract or urinary system, areas of potential leakage may be treated with the photosensitive dye and exposed to light. The resulting tissue strengthening may help seal small defects or reinforce suture lines, potentially reducing the incidence of post-operative leaks.

[0062] The in-vivo tissue strengthening system may also find application in facial plastic surgery. The photosensitive dye may be applied before or after plication. Light-induced cross-linking may then be used to strengthen the tissue, potentially enhancing the longevity of the lift and reducing the risk of suture pull-through.

[0063] In neurosurgery and spine surgery, the system may be employed for dura mater repair. After applying the photosensitive dye to the edges of a dural tear or to a dural graft, light exposure may initiate cross-linking. This process may strengthen the dura mater or graft material, potentially improving the watertight seal and reducing the risk of cerebrospinal fluid leaks.

[0064] The in-vivo tissue strengthening system may also be applied in hernia repair procedures. During hernia surgery, the photosensitive dye may be applied to the weakened abdominal wall tissue surrounding the hernia defect. After light-induced cross-linking, the strengthened tissue may provide a more robust foundation for suture placement or mesh attachment, potentially reducing the risk of hernia recurrence.

[0065] In all these and other applications, the use of the in-vivo tissue strengtheningsystem may be tailored to the specific needs of the procedure and the characteristics of the tissue being treated. The concentration of the photosensitive dye, the light exposure parameters, and the application technique may be adjusted to optimize the strengthening effect while ensuring patient safety.

[0066] In some cases, the use of photochemical cross-linking in living tissue may require careful consideration of safety and biocompatibility factors. The application of photosensitive dyes and exposure to light energy may potentially impact surrounding tissues and cellular processes. To address these concerns, various measures may be implemented to enhance safety and minimize potential adverse effects.

[0067] To mitigate potential phototoxicity, the light source parameters may be carefully controlled. In some cases, the wavelength, intensity, and duration of light exposure may be adjusted to minimize damage to surrounding healthy tissues while still achieving the desired cross-linking effect. The use of targeted light delivery systems, such as fiber optic probes or specialized applicators, may help confine the light exposure to the specific treatment area.

[0068] The system may be adapted for use in veterinary medicine. In some cases, species-specific dye formulations and light parameters may be developed to account for variations in tissue composition and healing processes across different animal species. In some cases, the tissue strengthening system may be integrated with imaging technologies to allow for real-time monitoring of the cross-linking process. This may involve the development of dye formulations that are visible under specific imaging modalities or the incorporation of sensors to detect changes in tissue properties during treatment.

[0069] The adaptability of the in-vivo tissue strengthening system may allow for its application across a wide range of surgical procedures and anatomical locations, potentially expanding its utility in various medical fields and improving outcomes in diverse patient populations. In some cases, the in-vivo tissue strengthening system may be integrated with existing surgical techniques to enhance tissue repair and improve surgical outcomes. The system may be used in conjunction with traditional suturing methods, potentially providing additional support and strength to the repaired tissue.

[0070] The light activation step of the tissue strengthening system may be performed at various points during the surgical procedure. In some cases, light exposure may occur immediately after dye application and before suture placement, allowing for tissuestrengthening prior to approximation. In other cases, light activation may be performed after suture placement, potentially enhancing the overall strength of the repair.

[0071] Non-Limiting, Example Clinical Applications

[0072] In some cases, the in-vivo tissue strengthening system may be applied in facelift procedures involving SMAS (Superficial Musculoaponeurotic System) plication, such as illustrated in Fig. 3A. The goal of SMAS plication in facelift surgery may be to achieve maximal durability and maintain long-term results. The SMAS layer and associated anatomical structures, including adhesions such as temporal adhesions and lateral orbital thickening, true ligaments such as zygomatic ligaments, masseteric ligaments, and mandibular ligaments, and the sub-SMAS plane, may be manipulated during facelift procedures. The layered anatomical relationship in the facial region includes the skin, the SMAS layer beneath the skin, the sub-SMAS plane beneath the SMAS, and the deep fascia underlying the sub-SMAS plane. By applying the photosensitive dye to the SMAS tissue and initiating photochemical cross-linking, the SMAS tissue may be strengthened, potentially improving resistance to suture pull-through and enhancing the durability of the plication. In some cases, the plication may utilize a series of interrupted sutures, such as five interrupted sutures, to secure the tissue. Thread sutures may also be used for measurement purposes, such as to assess tissue laxity over time. The sutures may be formed from various materials, such as high-strength, multi-strand, ultra-high molecular weight polyethylene (UHMWPE) core surgical sutures with or without a braided polyester jacket, such as FiberWire or other suitable suture materials. FiberWire® is a registered trademark of Arthrex, Inc. In some experimental studies, as shown in Fig. 3B, PTP treatment of SMAS tissue resulted in a 58% decrease in tissue laxity at 4 weeks and a 54% decrease in tissue laxity at 12 weeks compared to untreated controls. Additionally, PTP treatment of native human SMAS tissue demonstrated a 112% increase in modulus of elasticity, a 64% increase in maximum load, and a 55% increase in maximum stress compared to untreated tissue.

[0073] In some cases, the in-vivo tissue strengthening system may be applied in facelift procedures involving SMAS (Superficial Musculoaponeurotic System) plication. The goal of SMAS plication in facelift surgery may be to achieve maximal durability and maintain longterm results. The SMAS layer and associated anatomical structures, including adhesions such as temporal adhesions and lateral orbital thickening, true ligaments such as zygomaticligaments, masseteric ligaments, and mandibular ligaments, and the sub-SMAS plane, may be manipulated during facelift procedures. The layered anatomical relationship in the facial region includes the skin, the SMAS layer beneath the skin, the sub-SMAS plane beneath the SMAS, and the deep fascia underlying the sub-SMAS plane. By applying the photosensitive dye to the SMAS tissue and initiating photochemical cross-linking, the SMAS tissue may be strengthened, potentially improving resistance to suture pull-through and enhancing the durability of the plication. In some cases, the plication may utilize a series of interrupted sutures, such as five interrupted sutures, to secure the tissue. Thread sutures may also be used for measurement purposes, such as to assess tissue laxity over time. The sutures may be formed from various materials, such as high-strength, multi-strand, ultra-high molecular weight polyethylene (UHMWPE) core surgical sutures with or without a braided polyester jacket, such as FiberWire or other suitable suture materials. FiberWire® is a registered trademark of Arthrex, Inc. In some experimental studies, PTP treatment of SMAS tissue resulted in a 58% decrease in tissue laxity at 4 weeks and a 54% decrease in tissue laxity at 12 weeks compared to untreated controls. Additionally, PTP treatment of native human SMAS tissue demonstrated a 112% increase in modulus of elasticity, a 64% increase in maximum load, and a 55% increase in maximum stress compared to untreated tissue.

[0074] Non-Limiting, Example Studies

[0075] In some cases, experimental studies have been conducted to evaluate the efficacy of the in-vivo tissue strengthening system. These studies may involve both rat and swine models to assess the improvements in tissue strength and surgical outcomes compared to traditional techniques.

[0076] As one non-limiting example, testing was performed on rats. The testing assessed the biomechanical properties of the platysma muscle (SMAS) in rats, both before and after PTB treatment. The acquired data showed that the treated platysma tissue (n=4) exhibited a significantly higher modulus compared to non-treated control samples (n=4) (1681±740 vs. 902±291; p<0.05), along with a superior maximal load before tissue tearing (5.8±1.2 vs.2.4±0.6; p<0.01).

[0077] Next, a bilateral SMAS plication was performed in rats. One side of the face served as a control, while the other side was treated. After one month, a significant decrease in tissue laxity on the treated side was observed. Tissue laxity was determined by the distancethe sutures have moved away from each other over time.

[0078] Other non-limiting testing was performed with swine. Porcine Dura and Pericardium tissue samples were harvested. The tissues were cut into uniform 15x6 mm samples to assess their resistance to tearing when sutured. A single 4-0 Vicryl suture was placed 5 mm from the edge of each sample. In the control group (n=4), the suture was placed into the native, untreated tissue. In the treatment group [n=4], the tissue was treated before suture placement. For biomechanical testing, the sample was positioned between two grips: the suture-free end was secured in one grip, while the suture itself was secured in the other.

[0079] The maximum load prior to tissue tear was measured using a tensiometer after the application of tensile force. Subjective assessment revealed increased stiffness in the treated samples of Dura and Pericardium. The maximum load prior to tissue tearing was significantly higher in the treated dura samples (4.5±1.3 vs. 2.2±0.9, p<0.05] and treated pericardium samples (3.5±0.9 vs. 2.2±0.6, p<0.05) compared to the native, untreated tissue.

[0080] In some cases, the photosensitive dye used for PTP treatment may comprise a 0.1% Rose Bengal solution, which may be activated by green light from the excitation source. The concentration and light parameters may be adjusted based on the specific tissue being treated and the desired degree of strengthening.

[0081] Cyclic testing may be performed to evaluate the fatigue behavior and gap formation characteristics of treated tissue. In some cases, cyclic testing may involve subjecting the tissue to repeated loading cycles between a minimum load and a maximum load, such as between 2 N and 15 N, for a predetermined number of cycles, such as 2000 cycles. Gap formation may be recorded at a preload, such as 1 N, at various cycle intervals, such as at 0, 500, 1000, 1500, and 2000 cycles. In some cases, 500 cycles may correspond to approximately 5 to 10 days of active rehabilitation. For cyclic testing of tendon repairs, a modified Kessler suture technique may be employed, where the suture passes through the core of the tendon substance on either side of the transection site. Gap formation results may indicate that PTP-treated tissue reaches a clinically relevant gap formation threshold, such as 2 mm, at a slower rate or maintains smaller gaps throughout the testing period compared to untreated controls, as shown in Fig.4. The first 500 cycles represent the critical early phase where the most pronounced difference occurs, with treated samples showing approximately 5 mm gap formation versus approximately 8 mm for controls at 500cycles. Specific percentage reductions in gap formation at each cycle interval include -47% at 500 cycles, -37% at 1000 cycles, -35% at 1500 cycles, and -37% at 2000 cycles.

[0082] Degradation assay testing may be performed to evaluate the resistance of treated tissue to enzymatic breakdown. In some cases, tissue samples may be obtained using a punch biopsy, such as a 5 mm punch biopsy, and samples may be weight-matched to ensure consistent comparison between treated and control groups. The samples may be subjected to digestion with a collagenase enzyme, such as Collagenase Type I, and incubated at physiological temperature, such as 37°C, under continuous motion. The endpoint of the degradation assay may be the time to complete dissolution of the tissue sample. In some experimental studies, N=4 samples were tested, with control samples demonstrating a mean time to dissolution of approximately 258 minutes (SD=75 minutes), while PTP-treated samples demonstrated a mean time to dissolution of approximately 400 minutes (SD=66 minutes), representing a 55% increase in degradation resistance time.

[0083] Histological analysis may be performed to evaluate the structural changes in treated tissue. In some cases, standard histological staining techniques may be employed, such as hematoxylin and eosin (H&E) staining and Picrosirius red staining. Both cross-sectional and longitudinal sections may be examined to assess collagen fiber organization. Histological analysis of PTP-treated tissue revealed smoothening and tight packing of collagen fibers compared to untreated controls, indicating improved collagen organization resulting from the photochemical cross-linking process and not present in the untreated sample.

[0084] In some cases, PTP treatment of human SMAS tissue at the suture-tissue interface may demonstrate significant improvements in mechanical properties. In some experimental studies, PTP-treated human SMAS at the suture-tissue interface demonstrated a 139% increase and a 229% increase in relevant mechanical properties compared to untreated controls. Tissue laxity may be assessed by measuring the distance between marker threads placed in the tissue at the time of plication. Measurements may be taken at various time points, such as at 4 weeks and 12 weeks post-operatively, to assess the durability of the plication over time.

[0085] Animal models may be used to evaluate the efficacy of PTP treatment in a controlled experimental setting. In some cases, a rat model may be selected for SMASplication studies due to several advantages, including being relatively inexpensive, possessing platysma and SMAS-like tissue structures analogous to human anatomy, demonstrating good post-operative compliance, and providing measurable endpoints such as recurrent laxity of plication. A bilateral plication model may be employed, where one side of the animal serves as a control while the other side receives PTP treatment, providing an internally controlled comparison. In some cases, a small amount of skin may be excised during the procedure. For tendon studies, porcine hind-limb flexor tendons may be used, with each tendon halved for paired testing to provide matched control and treated samples. For load to failure testing, a single U-suture configuration with high-strength suture material may be employed and the sample tested until failure occurs.

[0086] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise. As used herein, "about", "approximately," "substantially," and "significantly" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" and "approximately" will mean up to plus or minus 10% of the particular term and "substantially" and "significantly" will mean more than plus or minus 10% of the particular term.

[0087] As used herein, the terms "include" and "including" have the same meaning as the terms "comprise" and "comprising." The terms "comprise" and "comprising" should be interpreted as being "open" transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms "consist" and "consisting of" should be interpreted as being "closed" transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term "consisting essentially of" should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

[0088] The phrase "such as" should be interpreted as "for example, including." Moreover, the use of any and all exemplary language, including but not limited to "such as", is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0089] Furthermore, in those instances where a convention analogous to "at least one of A, B and C, etc." is used, in general such a construction is intended in the sense of one having ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description or figures, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or"B" or "A and B."

[0090] All language such as "up to," "at least," "greater than," "less than," and the like, include the number recited and refer to ranges which can subsequently be broken down into ranges and subranges. A range includes each individual member. Thus, for example, a group having 1-3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 6 members refers to groups having 1, 2, 3, 4, or 6 members, and so forth.

[0091] A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims. The present invention has been described in terms of one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.

Claims

CLAIMS1. A system for in-vivo tissue strengthening at a tissue interface, comprising: a reservoir configured to hold a photosensitive dye;an excitation source;a pump configured to deliver the photosensitive dye to a surgical location including a tissue interface; anda control system configured to control operation of at least one of the excitation source and the pump to control one of delivery of the photosensitive dye or operation of the excitation source to safely deliver the photosensitive dye to in-vivo tissue at the surgical location or safely deliver light at a wavelength corresponding to an absorption spectrum of the photosensitive dye to initiate photochemical cross-linking in the in-vivo tissue at the surgical location including the tissue interface.

2. The system of claim 1, wherein the photosensitive dye comprises Rose Bengal.

3. The system of claim 1, wherein the excitation source comprises a lightemitting diode (LED) or laser diode configured to emit light between about 400 nm and about 700 nm.

4. The system of claim 1, wherein the control system is configured to adjust at least one of intensity or duration of light emitted by the excitation source to safely deliver light to the in-vivo tissue at the surgical location.

5. The system of claim 1, further comprising a scope configured to deliver the photosensitive dye and light from the excitation source to the surgical location.

6. The system of claim 1, further comprising an applicator configured to deliver the photosensitive dye and light from the excitation source to the surgical location.

7. The system of claim 1, further comprising a processing system configured to maintain pH of the photosensitive dye within a predetermined range.

8. The system of claim 7, wherein the photosensitive dye further comprises at least one of an antioxidant, a free radical scavenger, or a penetration enhancer.

9. The system of claim 8, wherein the photosensitive dye is formulated as a two-part system comprising the photosensitive dye and an activator kept separate until application.

10. A method for in-vivo tissue strengthening, comprising:applying a photosensitive dye to an in-vivo tissue interface at a surgical location; andexposing the tissue to light at a wavelength corresponding to an absorption spectrum of the photosensitive dye to initiate photochemical cross-linking in the in-vivo tissue interface and strengthen the in-vivo tissue interface against tearing or gap formation at the surgical location.

11. The method of claim 10, wherein the photosensitive dye comprises Rose Bengal.

12. The method of claim 10, further comprising engaging a surgical fixation system in the in-vivo tissue interface after photochemical cross-linking in the in-vivo tissue interface at the surgical location.

13. The method of claim 10, further comprising adjusting at least one of intensity or duration of the light exposure to control photochemical cross-linking in the in-vivo tissue interface at the surgical location.

14. The method of claim 10, wherein applying the photosensitive dye comprises delivering the dye through a scope to the surgical location.

15. The method of claim 14, wherein exposing the in-vivo tissue interface to light comprises delivering light through the scope to the surgical location.

16. The method of claim 10, further comprising preparing the photosensitive dye by combining the dye with an activator immediately prior to application.

17. A kit for in-vivo tissue strengthening, comprising:a photosensitive dye;a photoactivator system comprising an excitation source configured to emit light at a wavelength corresponding to an absorption spectrum of the photosensitive dye; anda controller configured to control the excitation source to safely deliver the photosensitive dye to in-vivo tissue a surgical location including a tissue interface.

18. The kit of claim 17, wherein the photosensitive dye comprises Rose Bengal.

19. The kit of claim 18, wherein the excitation source comprises a light-emitting diode (LED) or laser diode configured to emit light at a fluence of between 80-120 J / cm2or an irradiance between 01.-1.5 W / cm2.

20. The kit of claim 19, further comprising a scope configured to deliver both the photosensitive dye and light from the excitation source to the surgical location.

21. The kit of claim 17 further comprising at least one sensor configured to monitor the surgical location or tissue interface and provide feedback to the controller to maintain a desired surgical environment.

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