Wound scaffold material for suppressing scarring of biological tissue

Abstract

Provided is a technique for suppressing excessive scarring of biological tissue during the wound healing process. 【Solution】An artificial wound scaffold material applied to a biological injury has a bioabsorbable biomaterial and an antifibrotic agent as main components, and at least during the use of the wound scaffold material, the biomaterial contains the antifibrotic agent. The biomaterial functions as an artificial extracellular matrix having the property of adhering to progenitor cells of the body's myofibroblasts within the wound. The wound scaffold material is placed during use so as to locally contact a wound formed on the inner surface of a closed cavity in the body, whereby the antifibrotic agent and the biomaterial are locally administered to the wound, thereby enabling an anti-scarring treatment to be performed in a state of suppressing the delay of wound healing during the wound healing process.

Description

Technical Field

[0001] The present invention relates to a technique for suppressing excessive scarring of biological tissues during the wound healing process. and / or suppress adhesion between the abdominal wall and the target organ after laparotomy

Background Art

[0002] When a living body is locally damaged, a wound is formed. Here, "wound" has various definitions. For example, it means damage to the skin and soft tissues caused by external force.

[0003] "Wound" is classified, focusing on its cause of occurrence, into traumatic wounds caused by accidents and surgical wounds caused by surgical operations. Examples of surgical wounds include incisional wounds (e.g., wounds incised by surgery) and organ injuries (e.g., wounds occurring in intra-abdominal organs and peritoneum due to laparotomy).

[0004]

[0005] Also, "wound" is classified, focusing on the degree of damage, into defective wounds with tissue defects and non-defective wounds without tissue defects. Further, it is classified into shallow skin wounds where the damage only reaches the dermis and deep wounds where the damage reaches the subcutaneous tissue. A living body inherently has a natural healing ability. "Natural healing" has various definitions. For example, it means that damaged biological tissues are repaired by regeneration (i.e., scarless healing) or scar healing over time.

[0006] By the way, in the mechanism of wound healing, that is, in the process of natural healing of wounds in a living body, first, soft granulation having fibroblasts and abundant blood vessels is formed in the wound. Eventually, as the granulation decreases in blood vessels and fibroblasts produce collagen fibers, it is replaced by hard scar tissue. This is a phenomenon called fibrosis, and in parallel with this, the epithelium is regenerated.

[0007] ​A plurality of collagen fibers initially exist in a sparse state within granulation tissue, but eventually these collagen fibers become dense and homogenize. Such natural healing accompanied by fibrosis is namely scar healing, and the tissue formed by this process is scar tissue.

[0008] When scar tissue is formed within the dermis of the living body's skin and that scar tissue contracts or hypertrophies, problems such as restricted movement of the skin and inhibited function of the motor organs, as well as problems such as pain and mental distress associated with poor appearance, may be caused regardless of the degree of severity.

[0009] In addition, when scar tissue is formed within the living body's organs or viscera (for example, eyes, lungs, heart, intra-abdominal organs (such as the liver, kidneys, etc.), body cavities (abdominal cavity, thoracic cavity, mediastinum, etc.)), it may cause symptoms such as dysfunction or insufficiency.

[0010] Therefore, scarring of living tissue is an inevitable phenomenon that occurs during the wound repair process for the purpose of natural healing of the wound, but it is desirable to suppress excessive scarring to the extent that it does not inhibit the body's original natural healing function. For this reason, it is desirable to develop new technologies for suppressing such scarring.

[0011] Patent Document 1 discloses a technique for suppressing scarring of the human eye, which is a target site, caused by eye injuries, surgical incisions of the eye, etc., that is, an anti-scarring treatment method.

[0012] The same document further discloses, as the anti-scarring treatment method, a technique of locally administering an extracellular matrix (hereinafter also referred to as "ECM" or "extracellular matrix"), such as decorin, to the surface of the eye of a human patient, expecting its action as an anti-fibrotic agent.

[0013] In addition, the same document discloses a plurality of parameters worthy of attention for evaluating the occurrence of scarring, that is, as a plurality of evaluation parameters, ECM components that increase with scarring, myofibroblasts or the protein α-smooth muscle actin (α-SMA) that serves as a marker thereof and increases with scarring, TGF-β1 as a growth factor that promotes the transformation of fibroblasts and increases with scarring, and the like.

Prior Art Documents

Patent Documents

[0014]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0015] The present inventor has intensively studied a treatment method for suppressing scarring of biological tissues, and as a result, has found that administering an antifibrotic agent not on the surface of a biological wound but into the wound or intraperitoneally, and locally rather than systemically throughout the body, and at the initial stage of the wound is important for scarring suppression.

[0016] Furthermore, while the suppression of scarring of biological tissues by the present inventor has the advantage of suppressing, preventing, or treating fibrosis or fibrotic diseases, it has the disadvantage of delaying wound healing (for example, in situations where wounds such as defect wounds and deep wounds are the targets of healing). However, it has also been found that it is important to construct the treatment method in an individual-adaptive manner (for example, to adapt to the site, degree, and characteristics of the wound in each individual, and physiological characteristics such as the immunity of each individual).

[0017] Based on these findings, the present invention has been made with the object of suppressing excessive scarring of biological tissues during the wound healing process. and / or suppress adhesion between the abdominal wall and the target organ after laparotomy

Means for Solving the Problems

[0018] In order to solve this problem, according to one aspect of the present invention, there is provided an artificial wound scaffold material to be placed in the abdominal cavity to suppress adhesion in the abdominal cavity after laparotomy, the bioabsorbable biomaterial is configured to contain an anti-fibrotic agent, the biomaterial functions as an artificial extracellular matrix to which progenitor cells of the body's myofibroblasts adhere, and is configured to act as a cell culture scaffold material using a hydrogel as a base material, the anti-fibrotic agent has a molecular weight of 400 or less and inhibits the differentiation of the progenitor cells into myofibroblasts in the living body, thereby performing anti-fibrosis on the peritoneal side surgical wound, which is the surgical wound formed on the peritoneal side of the abdominal wall in the abdominal cavity, and the organ side surgical wound, which is the surgical wound formed on the target organ, the wound scaffold material is in the form of a sheet agent and is placed in the abdominal cavity between the peritoneum and the target organ, and on both sides of the wound scaffold material, in surface contact with the local peripheral region including the peritoneal side surgical wound of the peritoneum and the local peripheral region including the organ side surgical wound of the target organ, respectively, thereby providing a wound scaffold material capable of suppressing scarring of each surgical wound and suppressing adhesion between the abdominal wall and the target organ after laparotomy. The following aspects are obtained by the present invention. Each aspect is divided into paragraphs, each paragraph is numbered, and when necessary, the numbers of other paragraphs are cited. This is for facilitating the understanding of some of the technical features that the present invention can adopt and combinations thereof, and it should not be construed that the technical features that the present invention can adopt and combinations thereof are limited to the following aspects. That is, it should be construed that although not described in the following aspects, it is not prohibited to appropriately extract and adopt the technical features described in this specification or the drawings as the technical features of the present invention.

[0019] Furthermore, describing each paragraph in a form that cites the numbers of other paragraphs does not necessarily mean preventing the technical features described in each paragraph from being separated and made independent from the technical features described in other paragraphs. It should be construed that the technical features described in each paragraph can be appropriately made independent according to their nature.

[0020] (Aspect 1) An artificial scaffold material for a wound applied to a wound of a living body, which is mainly composed of a bioabsorbable biomaterial and an anti-fibrotic agent, and is configured such that at least during the use of the scaffold material for the wound, the biomaterial contains the anti-fibrotic agent, the biomaterial is configured to function as an artificial extracellular matrix having a property of adhering to progenitor cells of myofibroblasts of the living body in the wound during the use, The scaffold material for wound is placed in the wound during use and / or makes at least one of the following first contact: locally contacting an area of the inner surface of the abdominal wall of the living body that has a first wound site of the abdominal wall as the wound, and second contact: locally contacting an area of the outer surface of the target organ in the abdominal cavity that has a second wound site of the target organ as the wound. It is placed in the abdominal cavity so that the anti-fibrotic agent is locally administered into the wound, thereby enabling anti-scarring treatment during the healing process of the wound.

[0021] Here, the technical matter of "the scaffold material for wound is placed in the wound" and the technical matter of "the scaffold material for wound is placed in the abdominal cavity so that at least one of the following first contact: locally contacting an area of the inner surface of the abdominal wall of the living body that has a first wound site of the abdominal wall as the wound, and second contact: locally contacting an area of the outer surface of the target organ in the abdominal cavity that has a second wound site of the target organ as the wound is made" are both, in any case, ultimately common in that the anti-fibrotic agent and the biomaterial as components constituting the scaffold material for wound move from the initial placement position of the scaffold material for wound into the wound and are placed there. Therefore, these technical matters are either the same technical feature or, even if not, at least corresponding technical matters.

[0022] (Aspect 2) The scaffold material for wound according to Aspect 1, wherein the biomaterial mainly contains a protein, polysaccharide, or glycoprotein complex having a property of adhering to the progenitor cells.

[0023] (Aspect 3) The scaffold material for wound according to Aspect 1 or 2, wherein the biomaterial is in the form of a hydrogel, powder, or sponge, or has the form of a film or sheet and is flexible.

[0024] (Aspect 4) When the wound scaffold is implanted into the living body, the wound scaffold defines a space that is isolated from the surrounding tissue of the wound in the living body and into which the progenitor cells can enter. When the progenitor cells enter the space, the entered progenitor cells can react with the anti-fibrotic agent present in the wound scaffold, thereby inhibiting the transformation of the progenitor cells into myofibroblasts and enabling the anti-scarring treatment. The wound scaffold according to any one of Aspects 1 to 3.

[0025] (Aspect 5) The scaffold has a function of defining an administration route of the anti-fibrotic agent in the living body, a function of providing a scaffold for the progenitor cells from outside the living body, and a function of supplementing the wound from outside the living body with the artificial extracellular matrix as a substitute for the original extracellular matrix severed by the wound. The wound scaffold according to any one of Aspects 1 to 4.

[0026] (Aspect 6) The scaffold is configured to retain the anti-fibrotic agent at least until it is implanted from outside the living body into the living body. The wound scaffold according to any one of Aspects 1 to 5.

[0027] (Aspect 7) During the period when the wound scaffold is present in the living body, while the anti-fibrotic agent remains in the wound scaffold, progenitor cells in the living body penetrate from the surrounding tissue of the wound into the wound scaffold. Thus, in the wound scaffold, the progenitor cells react with the anti-fibrotic agent to inhibit the transformation into myofibroblasts. The wound scaffold according to any one of Aspects 1 to 6.

[0028] (Aspect 8) The progenitor cells are a cell population including at least fibroblasts or mesothelial cells among fibroblasts, mesothelial cells, mesenchymal stem cells, bone marrow-derived stem cells, pericytes, vascular endothelial cells, smooth muscle cells, and epithelial cells, and including those that differentiate into myofibroblasts in response to the stimulus of the wound. The wound scaffold according to any one of Aspects 1 to 7.

[0029] (Aspect 9) The wound dressing material according to any one of Aspects 1 to 8, wherein the wound is present in soft tissue on the body surface including the dermis and subcutaneous tissue, in a part of the subcutaneous or submuscular tissue that surrounds the implant, or in the abdominal cavity of the living body.

[0030] (Aspect 10) The wound dressing material according to any one of Aspects 1 to 9, wherein the wound dressing material is administered at the timing immediately after the injury of the wound or at the initial stage of wound healing.

[0031] (Aspect 11) The wound dressing material according to any one of Aspects 1 to 10, wherein the wound dressing material is administered before scar tissue is formed in the wound, before or after the wound is sutured, so that the wound dressing material is used to perform the anti-scarring treatment in advance.

[0032] (Aspect 12) The wound dressing material according to any one of Aspects 1 to 11, wherein after the scar tissue is formed in the wound and the wound heals naturally, the scar tissue is surgically removed from the living body, and then, after the new wound formed by the excision is sutured in the living body, the wound dressing material is administered to the wound surface of the new wound, so that the wound dressing material is used to perform the anti-scarring treatment afterwards.

[0033] (Aspect 13) The wound dressing material according to any one of Aspects 1 to 12, which is a first multi-agent mixed type prepared by mixing at the site where the anti-scarring treatment is performed in a state where at least one of the biomaterial and the anti-fibrotic agent is a liquid agent.

[0034] (Aspect 14) The biomaterial is a solid agent, The wound dressing material according to Aspect 13, wherein the anti-fibrotic agent is a liquid agent.

[0035] (Aspect 15) The wound scaffold material is the second multi-agent mixed type prepared by mixing the biomaterial and the antifibrotic agent, both of which are solid agents, in a state where a liquid is added as a solvent and at the site where the anti-scarring treatment is performed, according to any one of Aspects 1 to 14 of the wound scaffold material.

[0036] (Aspect 16) The wound scaffold material is the wound scaffold material according to any one of Aspects 1 to 15, including a scaffold material in which the biomaterial and the antifibrotic agent are pre-mixed and configured as a liquid agent or a solid agent of one agent.

[0037] (Aspect 17) The wound scaffold material is the wound scaffold material according to any one of Aspects 1 to 16, including a scaffold material configured as an injection agent to be injected into the gap between the wound surfaces facing each other in the wound.

[0038] (Aspect 18) The injection agent is injected into the gap of the wound using an injector. The injector is a housing part capable of housing the wound scaffold material, which responds to an external force and the wound scaffold material exits from the housing part in a required amount, and a discharge part capable of discharging a part of the wound scaffold material housed in the housing part that has exited from the housing part. The wound scaffold material according to Aspect 17 includes the above.

[0039] (Aspect 19) The housing part is a first part capable of housing the biomaterial, a second part capable of housing the antifibrotic agent, and a function of responding to the same first external force as the external force or a different second external force, mixing the biomaterial in the first part and the antifibrotic agent in the second part, thereby creating the wound scaffold material. The wound scaffold material according to Aspect 18 includes the above.

[0040] (Aspect 20) The scaffold material for wound is the scaffold material according to any one of Aspects 1 to 19, which includes a scaffold material configured as a liquid agent, a coating agent, a patch, or an aerosol agent that is locally applied to the wound surface of the wound, the inner surface of the abdominal wall, or the outer surface of the target organ.

[0041] (Aspect 21) The scaffold material for wound includes a scaffold material configured as the patch, The patch has a form of a flexible film or sheet and is configured to be inserted into the gap of the wound in a posture extending along the wound surface of the wound, or to be inserted into the abdominal cavity so as to locally cover the inner surface of the abdominal wall and / or the outer surface of the target organ. The scaffold material for wound according to Aspect 20.

[0042] (Aspect 22) The scaffold material for wound is configured as the patch, The patch is in a sheet form in a flexible state, The patch is used during the abdominal surgery of the living body, The abdominal surgery includes An incision step of incising the abdominal wall, thereby forming a first wound site at the incision; and A surgical step of introducing a surgical instrument from outside the body through the incision into the abdominal cavity to perform a surgical operation on the target organ in the abdominal cavity, thereby forming a second wound site on the outer surface of the target organ. And The patch is inserted into the abdominal cavity from outside the body through the incision during the surgical step, The patch is placed in the abdominal cavity so that at least one of a first contact in which the patch locally contacts the region of the inner surface of the abdominal wall where the abdominal wall includes the first wound site and a second contact in which the patch locally contacts the region of the outer surface of the target organ where the target organ includes the second wound site is made. The scaffold material for wound according to Aspect 20.

[0043] (Aspect 23) The anti-fibrotic agent contained in the patch is the wound scaffold material according to Aspect 22, which moves to the wound surfaces of the first wound site and the second wound site in the intraperitoneal indwelling state where the patch is indwelled in the abdominal cavity, and performs an anti-scarring treatment on the first and second wound sites.

[0044] (Aspect 24) The wound scaffold material is the wound scaffold material according to any one of Aspects 1 to 23, wherein when the wound is a defect wound accompanied by tissue defect, reconstruction of the defect wound is not performed, and the wound surface of the wound is exposed, its administration is contraindicated.

[0045] (Aspect 25) The wound scaffold material is the wound scaffold material according to any one of Aspects 1 to 24, which is prepared by using a plurality of types of commercially available pharmaceuticals for which safety and efficacy have been established for other uses as the biomaterial and the anti-fibrotic agent, respectively, and simply mixing the two.

[0046] (Aspect 31) An artificial wound scaffold material applied to a wound of a living body, comprising a bioabsorbable biomaterial and an anti-fibrotic agent as main components, and configured such that at least during use of the wound scaffold material, the biomaterial contains the anti-fibrotic agent, the biomaterial is configured to function as an object that retains the anti-fibrotic agent in the living body during use, and also function as an artificial extracellular matrix that has a property of allowing progenitor cells of the myofibroblasts of the living body to adhere and supporting the proliferation of the progenitor cells, during use, the wound scaffold material is indwelled in an incision wound formed in the skin as the wound, whereby the anti-fibrotic agent and the biomaterial are locally administered into the wound, thereby enabling an anti-scarring treatment to be performed in a state of suppressing delay in wound healing during the wound healing process of the wound, the wound scaffold material further has, a feature that the wound does not include a wound formed by a surgical operation on the eye of the living body, and a feature that the wound does not include a defect wound comprising the wound scaffold is placed in the wound such that the anti-fibrotic agent is locally administered at a position isolated from the epithelium of the skin. The wound scaffold is a wound scaffold placed in the wound at an early stage of the wound healing process.

[0047] (Aspect 32) An artificial wound scaffold applied to a wound of a living body, the wound includes an incisional wound formed as an intact wound on the skin of the living body, the wound scaffold is mainly composed of a bioabsorbable biomaterial and an anti-fibrotic agent, and is configured such that at least during use of the wound scaffold, the biomaterial contains the anti-fibrotic agent. the wound scaffold is placed in the incisional wound during use, whereby the anti-fibrotic agent and the biomaterial are locally administered into the incisional wound, thereby enabling an anti-scarring treatment for the incisional wound to be performed in a state of suppressing delay in wound healing during the healing process of the incisional wound.

[0048] (Aspect 33) The wound scaffold according to Aspect 32, wherein the biomaterial functions as an object that retains the anti-fibrotic agent in the living body during use, and has a property of allowing progenitor cells of the myofibroblasts of the living body to adhere and supporting the proliferation of the progenitor cells, and is configured to function as an artificial extracellular matrix.

[0049] (Aspect 34) The wound scaffold according to Aspect 32 or 33, wherein the wound scaffold is placed in the incisional wound such that the anti-fibrotic agent is locally administered at a position isolated from the epithelium of the skin.

[0050] (Aspect 35) The wound scaffold according to any one of Aspects 32 to 34, wherein the wound scaffold is placed in the incisional wound at an early stage of the healing process of the incisional wound.

[0051] (Aspect 41) An artificial scaffold material for a wound applied to a wound of a living body, which is mainly composed of a bioabsorbable biomaterial and an antifibrotic agent, and is configured such that at least during use of the scaffold material for the wound, the biomaterial contains the antifibrotic agent, the biomaterial is configured to function as an artificial extracellular matrix having a property of adhering to progenitor cells of myofibroblasts of the living body at the wound during the use, the scaffold material for the wound is placed so as to locally contact a wound formed on the inner surface of a closed cavity in the living body during the use, whereby the antifibrotic agent and the biomaterial are locally administered to the wound, thereby enabling an anti-scarring treatment to be performed in a state of suppressing delay in wound healing during the wound healing process. A scaffold material for a wound.

[0052] (Aspect 42) The scaffold material for a wound according to Aspect 41, wherein the closed cavity includes the abdominal cavity of the living body.

[0053] (Aspect 43) The scaffold material for a wound according to Aspect 41, wherein the closed cavity includes a dissection cavity artificially formed in the living body for breast reconstruction or breast augmentation, and an implant is installed therein.

[0054] (Aspect 44) The scaffold material for a wound according to any one of Aspects 41 to 43, wherein the scaffold material for a wound has a function of defining an administration route of the antifibrotic agent in the living body, a function of providing a scaffold for the progenitor cells from outside the living body, and a function of supplementing the wound from outside the living body with the artificial extracellular matrix as a substitute for the original extracellular matrix severed by the wound.

[0055] (Aspect 45) The scaffold material for a wound according to any one of Aspects 41 to 44, wherein the scaffold material for a wound includes a scaffold material configured as a liquid agent, a coating agent, a patch agent, or an aerosol agent locally applied to the inner surface of the closed cavity.

[0056] (Aspect 46) The wound scaffold material includes a scaffold material configured as the adhesive, The adhesive has a form of a flexible film or sheet and is configured to locally cover the inner surface of the closed cavity during use, and the wound scaffold material according to Aspect 45.

[0057] (Aspect 47) The wound scaffold material is the wound scaffold material according to any one of Aspects 41 to 46, which is placed on the wound at the initial stage of the wound healing process.

[0058] (Aspect 48) The wound is the wound scaffold material according to any one of Aspects 41 to 47, including a non-defective wound.

Brief Description of the Drawings

[0059]

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[0060] Hereinafter, some exemplary embodiments of the present invention will be described in detail based on the drawings.

[0061] <Overview>

[0062] First, regarding the wound scaffold material according to these embodiments and the anti-scarring treatment method using the same, which is a treatment method or therapy (hereinafter, also referred to as "this treatment method") for suppressing tissue scarring in the wound healing process, a technical overview common to these embodiments will be described.

[0063] The purpose of the present inventor's proposal of this treatment method is to suppress the differentiation (transformation) of fibroblasts into myofibroblasts using fibroblasts as exemplary progenitor cells, thereby realizing scarless wound healing (such as scarless wound healing, scarless healing, wound healing without leaving a scar, scarless healing, mild scar healing, scarring suppression therapy, etc.).

[0064] According to the general theory, in the wound healing process, mainly due to TGF-β1 (an example of a growth factor that promotes the transformation of fibroblasts) stimulation, fibroblasts differentiate into myofibroblasts, and these myofibroblasts secrete excessive ECM (such as collagen), thereby forming a scar. However, in conventional anti-scarring treatment methods (such as taping and compression therapy, etc.), the scarring suppression effect is limited, and it was inevitable that a scar would remain after surgery or trauma.

[0065] On the other hand, drugs that suppress differentiation into myofibroblasts have already been approved in multiple numbers in this country under names such as antifibrotic agents and ROCK inhibitors (Rho kinase inhibitors). For example, their efficacy and safety have been established for diseases such as pulmonary fibrosis and glaucoma.

[0066] In contrast, the present inventors considered that by combining an antifibrotic agent containing such an approved drug non-exclusively with a biomaterial and applying it to the field of medicine related to wound healing, a safe and effective anti-scarring treatment method can be realized.

[0067] <General Discussion>

[0068] 1. Background

[0069] In humans as an example of a living body, when the skin is damaged after birth, the damaged part always heals with a scar remaining, and in the process of wound healing, unsightly scars such as hypertrophic scars and keloids often occur. Although various devices have been made in terms of suturing methods and aftercare to make the scars less noticeable, the scarring suppression effect of conventional anti-scarring treatment methods is limited, and a new anti-scarring treatment method is required. In particular, unsightly scars exposed on the face, hands, etc. bring great psychological pain and social stigma, significantly reducing the QOL (Quality of Life) of patients. "Scarless wound healing" is the wish of many patients who have suffered trauma or surgery, and its realization is eagerly desired.

[0070] As conceptually shown in FIG. 1 for the basic wound healing process, in the wound healing process, fibroblasts, which are an example of the progenitor cells, mainly differentiate into α-SMA-positive myofibroblasts by stimulation with TGF-β1, and scars are formed by the excessive secretion of ECM by these myofibroblasts.

[0071] The myofibroblasts cause scar contracture by contracting granulation tissue. The myofibroblasts are also abundant in the histological images of abnormal scars such as hypertrophic scars and keloids, and recent single-cell analysis has suggested that a subpopulation of fibroblasts with myofibroblast characteristics may contribute to keloid development.

[0072] On the other hand, as drugs that suppress the differentiation of fibroblasts into myofibroblasts, pirfenidone for pulmonary fibrosis (which regulates the production of cytokines and growth factors) and nin Te danib (a tyrosine kinase inhibitor) have already been approved in this country, and their efficacy and safety have been established.

[0073] In addition, ROCK inhibitors can also suppress the differentiation into myofibroblasts through the control of the cytoskeleton. As those classified as ROCK inhibitors, lipasudil for glaucoma and fasudil for cerebral vasospasm have been approved.

[0074] 2. Problems

[0075] The present inventor considered that these existing drugs that suppress the differentiation into myofibroblasts, as well as other existing drugs and late-stage drugs that can be substituted (hereinafter, collectively referred to as "antifibrotic agents"), could be applied to scar treatment.

[0076] Furthermore, the present inventor considered that by devising a local administration form by combining an antifibrotic agent and a biomaterial, side effects could be reduced compared to systemic administration of each drug, and set the following "problems".

[0077] (1) What kind of biomaterial is optimal for allowing an antifibrotic agent to act on a wound?

[0078] (2) Can scarless wound healing be achieved by using an antifibrotic agent on a wound?

[0079] To solve these "problems", the present inventor conducted intensive research prior to the completion of the present invention.

[0080] 3. Objectives and Effects of This Treatment Method

[0081] The objective of this treatment method is to achieve scarless wound healing by a unique approach of suppressing the differentiation from fibroblasts to myofibroblasts using an antifibrotic agent.

[0082] To achieve this objective, as conceptually shown in FIG. 2, this treatment method uses an artificial scaffold material devised to realize an administration form in which an antifibrotic agent is locally administered to the wound to be healed, and contains a preferably configured biomaterial and a preferably selected antifibrotic agent, and is characterized by suppressing excessive scarring of tissues during the wound healing process.

[0083] According to this treatment method, not only can scarless wound healing be achieved, but it may also greatly contribute to the progress of wound treatment as a fundamental therapeutic and preventive agent for keloids and hypertrophic scars.

[0084] Furthermore, according to this treatment method, when an existing drug whose safety has already been verified is used as an antifibrotic agent, if the usefulness or efficacy of the existing drug is additionally verified, it can be expected that this treatment method will be clinically applicable at an early stage.

[0085] Therefore, according to this treatment method, it is expected that an artificial scaffold material having an antifibrotic effect will be useful for preventing adhesions after laparotomy and preventing contracture of breast implants, and may be widely applied in the surgical field.

[0086] 4. Background of the Idea of This Treatment Method

[0087] As a doctor, the inventor has come into contact with many patients who hope for scar treatment, complaining of functional disorders, pain, and mental distress caused by scars after trauma or surgery (for example, scars caused by trauma or surgical incisions) in daily clinical practice in the field of plastic surgery, and realizes that the achievement of scarless wound healing is an important issue in the field of plastic surgery.

[0088] Furthermore, since the effects of conventional symptomatic treatments for keloids and hypertrophic scars are limited, the inventor feels that a new treatment method based on molecular mechanisms is necessary.

[0089] Therefore, as a preliminary experiment, the inventor observed the distribution of α-SMA-positive myofibroblasts in the tissue images of mature scars and immature scars by immunohistochemistry (IHC). As a result, the inventor obtained the finding that myofibroblasts are localized in the deep part of immature scars and do not exist at all in mature scars.

[0090] Based on this finding, the inventor considered that myofibroblasts appear in the initial stage of wound, secrete ECM, and after the ECM forms a scar, they disappear by apoptosis or the like as the scar matures.

[0091] Then, the inventor conceived that if the differentiation into myofibroblasts can be suppressed at the initial stage of wound, excessive production of ECM will not occur and scarless wound healing will be possible.

[0092] Furthermore, when the inventor observed α-SMA-positive myofibroblasts in keloid tissue by immunostaining, the inventor obtained the finding that myofibroblasts are distributed over a wide range of keloid lesions (for example, a region with an area of more than half of the total area).

[0093] Based on this finding, the inventor considered that keloid is a pathological condition in which differentiation into myofibroblasts constantly occurs due to continuous stimulation by mechanical stress or TGF-β1, and that suppression of differentiation into myofibroblasts can also be applied to the treatment of keloids.

[0094] By the way, regarding the antifibrotic agent, since there are reports of side effects caused by systemic administration, in reality, it is difficult to perform systemic administration only for aesthetic improvement.

[0095] However, as conceptually shown in FIG. 2, the present inventors considered that by locally administering the antifibrotic agent in combination with a biomaterial that functions as an artificial ECM contributing to the proliferation of the progenitor cells to a wound, it may be possible to use it while reducing the risk of side effects as much as possible.

[0096] 5. Configuration of the Scaffold Material

[0097] (1) Overall Configuration

[0098] The scaffold material has a configuration in which a biomaterial that functions as an artificial ECM for the progenitor cells and an antifibrotic agent are each the main component, and the antifibrotic agent is contained in the biomaterial.

[0099] The scaffold material may contain, as other components, auxiliary components or additives, for example, stabilizers, preservatives, solvents, thickeners, etc. Further, the scaffold material may be a solid or a liquid having a high viscosity, or may be a liquid having a low viscosity such as water.

[0100] The scaffold material is configured such that, for example, the antifibrotic agent and the biomaterial can act simultaneously, that is, simultaneously and in parallel, without taking measures such as time-lag elution in which each component is encapsulated in microspheres to make the elution timing different from each other.

[0101] (2) Types Regarding Structure

[0102] a. Liquid Injection Type

[0103] In the liquid injection type, as conceptually shown in FIG. 3, the scaffold material is configured as a liquid agent (including gel) injected into the gap between the wound surfaces (each of a pair of surfaces facing each other with a gap in the wound) using an injector.

[0104] Examples of the injector include a syringe that pushes a pressing piston into a cylinder to extrude a required amount of the liquid agent in the cylinder, and a syringe that compresses a flexible storage part containing the liquid agent by hand to reduce its volume and extrudes a required amount of the liquid agent from the storage part.

[0105] b. Sheet agent insertion type

[0106] In the sheet agent insertion type, as conceptually shown in FIG. 4, the scaffold material is a flexible sheet agent (a solid agent including a bioabsorbable film, tape, cloth, etc.) inserted into the wound surface gap or other sites, such as the abdominal cavity, and an antifibrotic agent is contained, adhered, coated, or attached thereto. The sheet agent is composed of a flexible substrate (support matrix) made of a biomaterial and an antifibrotic agent is contained therein.

[0107] (3) Types of liquid injection type

[0108] The scaffold material of the liquid injection type can be of a single-component type or a two-component mixed type (an example of a multi-component mixed type).

[0109] In the single-component type, before arriving at the site where the anti-scar treatment is performed, the scaffold material is composed of a mixture of a biomaterial and an antifibrotic agent as a single liquid. In this case, the scaffold material can be commercially available as a finished product.

[0110] On the other hand, the two-component mixed type can be of type 1-3 in which at least one of the biomaterial and the antifibrotic agent is a liquid agent, and type 4 in which both are powder agents, as shown in tabular form in FIG. 5. In this case, the scaffold material can be commercially available as a semi-finished product or a kit product, with or without combination with the injector.

[0111] Among the two-agent mixing types, in Types 1-3, at the site where the anti-scarring treatment is performed, the biomaterial and the anti-fibrotic agent are mixed to form a single liquid.

[0112] In contrast, in Type 4, at the site where the anti-scarring treatment is performed, a liquid (such as physiological saline, purified water, etc.) as a common solvent for the biomaterial and the anti-fibrotic agent is added to at least one of the biomaterial and the anti-fibrotic agent, and the biomaterial and the anti-fibrotic agent are mixed to form a single liquid.

[0113] (4) Sheet Insertion Type

[0114] An example of the sheet insertion type is a first sheet insertion type in which a sheet agent as a scaffold is inserted and left in the wound surface gap, as conceptually shown in FIGS. 4(a) and (b). In this type, the scaffold is inserted and left in the wound surface gap so as to substantially have no protrusion from the body surface.

[0115] In FIG. (a), a first example in which the sheet agent is inserted into the wound surface gap exposed on the body surface is conceptually shown in a perspective view. On the other hand, in FIG. (b), a second example in which the sheet agent is inserted into the peeling cavity (to be described in detail later) formed as a wound surface gap under the muscular layer (subcutaneous is also possible) when an implant is left is conceptually shown in a cross-sectional view.

[0116] Here, the second example will be described in detail.

[0117] In this example, as shown in the cross-sectional view of FIG. (b), the sheet agent is used when inserting and leaving an implant under the human subcutaneous or muscular layer.

[0118] An example of such an implant is a breast implant, which generally has a partial spherical shape and is inserted and retained in a cavity artificially formed within the human breast (a cavity formed between two tissues by separating one tissue from the other, also referred to as a "dissection cavity"). Thereby, breast reconstruction or breast augmentation is performed.

[0119] In the application of breast reconstruction or breast augmentation, the implant is a soft capsule-shaped medical device filled with silicone gel or the like.

[0120] An example of the dissection cavity is, as shown in the figure, formed under the pectoral muscle of a human (for example, under the pectoralis major muscle, that is, between the pectoral muscle and the chest wall). In this example, the implant is inserted under the pectoralis major muscle.

[0121] Another example of the dissection cavity, although not shown in the figure, is formed under the mammary gland. In this example, the implant is inserted under the mammary gland.

[0122] In any example, the tissue (hereinafter referred to as the "target tissue") with which the surface of the implant should come into contact is damaged due to separation from other tissues, and wounds are formed over the entire separation surface of the target tissue. Since the wounds cause scarring, it is desirable to perform anti-scarring treatment.

[0123] Therefore, in this example, the implant is inserted and retained in the dissection cavity with its surface (ideally, the entire surface) covered by the aforementioned sheet agent. In the retained state, the anti-fibrotic agent contained in the sheet agent covering the implant moves to the surface of the target tissue forming the dissection cavity and is applied over substantially the entire surface thereof (ideally, over the complete entire surface). As a result, scarring of the dissection cavity is suppressed.

[0124] In this example, the fact that the surface of the implant is coated with the sheet agent corresponds to an example in which the scaffold material is inserted in a posture extending along the wound surface (for example, the surface of the major pectoralis muscle damaged by detachment and the surface of the chest wall damaged by detachment) of the wound within the gap of the wound (for example, the gap between the surface of the major pectoralis muscle damaged by detachment and the surface of the chest wall damaged by detachment), and also corresponds to an example in which the scaffold material is locally administered into the wound (for example, not to the entire breast area).

[0125] Although the first sheet agent insertion type has been described in detail above, as another example, as conceptually shown in FIGS. (c)-(e), there is a second sheet agent insertion type in which the sheet agent as the scaffold material is inserted into the abdominal cavity and left there for intra-abdominal placement.

[0126] In FIG. (c), the relative positional relationship between the exposed incision wound and the sheet agent left in the abdominal cavity during laparotomy is shown in an upper perspective view.

[0127] In FIG. (d), a third example in which the sheet agent is left in the abdominal cavity of the living body during abdominal closure is conceptually shown in a cross-sectional view. Also, in FIG. (e), a fourth example in which the sheet agent is left straddling two target organs in the abdominal cavity is conceptually shown in a perspective view.

[0128] In the third example shown in FIG. (d) and the fourth example shown in FIG. (e), the intra-abdominal laparotomy includes an incision step of incising the abdominal wall of the patient, thereby forming a first wound site (for example, a skin-side wound site) at the incision part (incision wound), and a surgical step of introducing a surgical instrument from outside the body through the incision part of the abdominal wall into the abdominal cavity to perform a surgical operation on the target organ, thereby forming a second wound site (for example, an intra-abdominal organ-side wound site) on the outer surface of the target organ.

[0130] The sheet agent is inserted into the abdominal cavity through the incision part from outside the body in the surgical step.

[0131] In the third example shown in FIG. (d), the sheet agent is placed in the abdominal cavity so that a first contact (e.g., surface contact) is made locally with the region of the peritoneum that includes the first wound site.

[0132] In this example, when the anti-fibrotic agent contained in the sheet agent is in the state of being placed in the abdominal cavity where the sheet agent is placed, and when the surface of the sheet agent contacts the peritoneum, it moves from the sheet agent to the wound surface of the first wound site and performs an anti-scarring treatment on the first wound site.

[0133] In the fourth example shown in FIG. (e), the sheet agent is placed in the abdominal cavity so that both a first contact (e.g., surface contact) that is made locally with the region of the peritoneum that includes the first wound site and a second contact (e.g., surface contact) that is made locally with the region of the outer surface of the target organ that includes the second wound site are made.

[0134] When the anti-fibrotic agent contained in the sheet agent is in the state of being placed in the abdominal cavity where the sheet agent is placed, and when the surface of the sheet agent contacts the peritoneum, it moves from the sheet agent to the wound surface of the first wound site and performs an anti-scarring treatment on the first wound site. On the other hand, when the back surface of the sheet agent contacts the outer surface of the target organ, it moves from the sheet agent to the wound surface of the second wound site and performs an anti-scarring treatment on the second wound site.

[0135] More specifically, as shown in FIG. (e), the sheet agent is placed on two surfaces of those target organs straddling two target organs in the abdominal cavity. FIG. (e) shows in perspective view the state in which the scaffold material is placed on the surfaces of two target organs in the abdominal cavity straddling them.

[0136] In this example, when the sheet agent is configured as a single sheet member, the sheet agent comprehensively performs the first contact for anti-scarring treatment on the incision of the abdominal wall (surgical wound), that is, the first wound site, the second contact for anti-scarring treatment on the outer surface of the first target organ in the abdominal cavity, and the second contact for anti-scarring treatment on the outer surface of the second target organ in the abdominal cavity.

[0137] In addition, although FIG. (e) shows the state where two target organs are sutured, examples of the two organs for which such a procedure is performed include, for example, a combination of the stomach and the small intestine, and a combination of the liver and the intestinal tract.

[0138] Furthermore, in some of the above examples, intraperitoneal local administration using the sheet agent for anti-scarring treatment is performed at least for the first wound site. In addition to this, for example, for the first wound site, additionally, the aforementioned liquid injection type may be adopted, and a liquid agent as a scaffold material may be locally administered into the wound at the first wound site using an injector.

[0139] In short, the sheet agent shown in FIG. (e) constitutes an example of a concentrated anti-scarring treatment type patch that performs both the first contact and the second contact using a single sheet member.

[0140] By the way, in the third and fourth examples, since the sheet agent is composed of at least a biomaterial, that biomaterial may be associated with the possibility of promoting the healing of the abdominal wall and the intraperitoneal organs.

[0141] However, it should be noted that the sheet agent exerts the action of a physical spacer that physically separates the abdominal wall and the intraperitoneal organs, rather than the action of such healing, and the action of routing (path definition) that induces an anti-fibrotic agent to the target site (in the abdominal wall, it is the opening on the abdominal cavity side of the first wound site, and in the intraperitoneal organ, it is the opening on the abdominal cavity side of the second wound site).

[0142] Therefore, if the sheet agent is placed intraperitoneally, particularly at a position between the abdominal wall and the intraperitoneal organs, not only the effect of suppressing scarring of each of the abdominal wall and the intraperitoneal organs can be obtained, but also the effect of preventing adhesion between the abdominal wall and the intraperitoneal organs after surgery can be obtained.

[0143] In the present specification, the "target organ" may be defined as an intraperitoneal organ on which a surgical operation is performed, or may be defined as an intraperitoneal organ that does not undergo a surgical operation but comes into contact with the scaffold material.

[0144] Hereinafter, several other examples of the second sheet agent insertion type will be described.

[0145] In one example, although not shown, the sheet agent has a first sheet member and a second sheet member that are independent of each other. The first sheet member locally contacts a region including a first wound site in the abdominal wall on its surface. The second sheet member is configured to locally contact a region including a second wound site of a target organ in the abdominal cavity on its back surface.

[0146] In this example, the anti-fibrotic agent contained in the sheet agent moves from the first sheet member to the wound surface of the first wound site and performs an anti-scarring treatment on the first wound site when the sheet agent is in the intraperitoneal placement state and the surface of the first sheet member contacts the inner surface of the abdominal wall. On the other hand, when the back surface of the second sheet member contacts the outer surface of the target organ, it moves from the second sheet member to the wound surface of the second wound site and performs an anti-scarring treatment on the second wound site.

[0147] As a precautionary note, the biomaterial contained in the same sheet agent also moves from the first sheet member to the wound surface of the first wound site and from the second sheet member to the wound surface of the second wound site, and thus has the same material movement characteristics as the anti-fibrotic agent.

[0148] In short, in this example, the sheet agent constitutes an example of a dispersive anti-scarring treatment type patch in which the first contact and the second contact are performed separately at discrete locations using separate sheet members (a plurality of sheet members independent of each other).

[0149] By the way, in the plurality of examples described above for the first and second sheet agent insertion types, since the sheet agents are all flexible and have shape retention (the property that the shape does not change without external force), they can be placed in surface contact with a curved anti-scarring treatment surface such as the inner surface (inner surface) of the abdominal wall and the outer surface (outer surface) of the organ.

[0150] Thus, as an advantage of using the sheet agent for anti-scarring treatment, since it has the property that its own shape easily follows the surface of the placement location, there is an advantage that it can be placed in surface contact with a curved anti-scarring treatment surface.

[0151] Generally, when a local injury, for example, a surgical wound, is formed on the surface of an organ in the abdominal cavity, scarring is initiated at that location in the organ, and the scarring has the characteristic of spreading planar on the surface of the organ.

[0152] Therefore, as an advantage of using the sheet agent for anti-scarring treatment, since the sheet agent can be locally applied to the surface of the organ so as to cover not only the damaged part but also its peripheral region, there is an advantage that it is easy to effectively suppress the spread of scarring on the surface of the organ.

[0153] (5) Materials that can be used as constituent materials of biomaterials

[0154] The biomaterials mainly contain proteins (e.g., collagen, elastin, gelatin), polysaccharides (e.g., hyaluronic acid, chondroitin sulfate, cellulose), or glycoprotein complexes (e.g., aggrecan, versican). The biomaterials are in the form of hydrogels, powders, sponges, or sheets, and have flexibility and shape retention.

[0155] There are no particular limitations on the materials that make up the biomaterials, so long as they are materials that can be dissolved, decomposed, metabolized, or absorbed by cells, microorganisms, or living organisms through their inherent life activities.

[0156] Furthermore, examples of commercially available drugs (medical products, etc.) that constitute the biomaterial include collagen sponges (e.g., Pelnac (registered trademark), Terdermis (registered trademark)), collagen sheets (e.g., Integra (registered trademark)), gelatin hydrogels (e.g., Genocel (registered trademark)), gelatin sponges (e.g., Spongel (registered trademark)), etc.

[0157] (6) Drugs that can be used as antifibrotic agents

[0158] Antifibrotic agents include fasudil, ripasudil, pirfenidone, and nin. Te It is possible to use low molecular weight agents such as danib. The antifibrotic agent can be liquid, powder or particulate. The concentration of the antifibrotic agent can vary depending on the type of antifibrotic agent, the type of wound, the extent of the wound and the characteristics of the individual (organism, human) to be administered.

[0159] 6. Basic guidelines for experimental methods

[0160] (1) Purpose

[0161] As a treatment method for a living body, for example, a human subject, to confirm the effectiveness as a drug when an anti-fibrotic agent, which has been established to be effective and safe in relation to other uses (for example, treatment of other diseases) and is commercially available, is applied to the skin of a living body for anti-scarring treatment in this treatment method together with a biomaterial (the safety is naturally affirmed without the need for an experiment because it is commercially available), an animal experiment using a scaffold material as an invention product is conducted as an in vivo test to confirm the anti-scarring effect of the anti-fibrotic agent.

[0162] (2) Outline of the experiment

[0163] Treatment experiment on a mouse wound model

[0164] An incision wound reaching from the epidermis to the fascia is created on the back of a mouse, and the incision wound is sutured and fixed. Thereafter, a mouse wound model is created in a state where a scaffold material containing an anti-fibrotic agent is locally administered and left in the wound gap within the incision wound (within the gap between a pair of wound surfaces facing each other with a gap in the incision wound, within the dermal gap, etc.).

[0165] Therefore, it is expected that myofibroblasts will be formed in the region from the boundary layer between the epidermis and the dermis to the fascia on the wound surface.

[0166] (3) Setting of the control group

[0167] As two types of control groups, Control group 1: A group in which the wound is simply sutured without administering either the biomaterial or the anti-fibrotic agent, and Control group 2: A group in which purified water is contained in a biomaterial not containing an anti-fibrotic agent and is administered into the wound as a gel-like scaffold material (without an anti-fibrotic agent) are set. In each control group, three mice are used.

[0168] Here, to explain the significance of each control group, control group 2, by comparison with control group 1, has the significance of enabling the confirmation of the pros and cons obtained solely by the biomaterial among the scaffolds when the scaffold as the invention product is applied to the wound.

[0169] (4) Setting of treatment groups

[0170] As two types of treatment groups, Treatment group 1: A gel-like scaffold (with an anti-fibrotic agent) containing a first anti-fibrotic agent (for example, fasudil) at a predetermined concentration in the biomaterial is administered into the wound, and Treatment group 2: A gel-like scaffold (with an anti-fibrotic agent) containing a second anti-fibrotic agent (for example, lipasudil) at a predetermined concentration in the biomaterial is administered into the wound are set. In each treatment group, three mice are used.

[0171] Here, it should be noted that the scaffold as the invention product contains an anti-fibrotic agent, while the scaffold used in the experiment does not contain an anti-fibrotic agent for the control group and contains an anti-fibrotic agent only for the treatment group.

[0172] Also, to explain the significance of each treatment group, treatment group 1, by comparison with control group 1, has the significance of enabling the confirmation of the effect when the scaffold as the invention product has a biomaterial and a first anti-fibrotic agent, and by comparison with control group 2, has the significance of enabling the confirmation of the pros and cons obtained solely by the first anti-fibrotic agent among the scaffolds as the invention product, and by comparison with treatment group 2, has the significance of enabling the relative confirmation of the pros and cons obtained solely by the first anti-fibrotic agent among the scaffolds as the invention product with respect to the pros and cons obtained solely by the second anti-fibrotic agent among the scaffolds as the invention product.

[0173] In addition, Treatment Group 2 has the significance of enabling the confirmation of the effect when the scaffold material as the invention product has a biomaterial and a second antifibrotic agent through comparison with Control Group 1, the significance of enabling the confirmation of the pros and cons obtained solely by the second antifibrotic agent among the scaffold materials as the invention product through comparison with Control Group 2, and the significance of enabling the relative confirmation of the pros and cons obtained solely by the second antifibrotic agent among the scaffold materials as the invention product with respect to the pros and cons obtained solely by the first antifibrotic agent among the scaffold materials as the invention product through comparison with Treatment Group 1.

[0174] (5) Incision and suture

[0175] As skin incisions for mice, two wounds per mouse are finally created to be "skin suture wounds". Specifically, at a length of 10 mm and the depth of the entire skin layer on the shaved back of the mouse, two incisions are made per individual. Then, each wound is sutured with 2 stitches only on the epidermis using a suture thread (for example, 6-0 nylon thread).

[0176] (6) Local administration of the scaffold material

[0177] Immediately after the suturing, for each of Control Group 2, Treatment Group 1, and Treatment Group 2, a single administration into the wound is performed using a gel-like scaffold material, such as by using the injector. With the above, one treatment is completed for each mouse. In each single administration into the wound, at the initial stage of the healing process of each skin suture wound (for example, immediately after the skin incision of the mouse), the scaffold material is locally administered and retained at a position isolated from the epidermis, that is, the epithelium, as shown in the two figures on the right in FIG. 7.

[0178] (7) Appearance evaluation and collection of scar tissue

[0179] After the surgery, the appearance of the surface (exposed surface) of the incision and the collection of scar tissue from each mouse are performed. The caudal wound of each mouse was collected on the 3rd day after the treatment, and the cranial wound was collected on the 7th day after the treatment.

[0180] (8) Specimen collection and scar tissue evaluation

[0181] For each group, one tissue specimen per scar tissue was collected and fixed in formalin and embedded in paraffin. For each tissue specimen, the scar tissue was evaluated.

[0182] As the evaluation method, the cross-sectional area of the scar was measured for each tissue specimen, and immunohistochemical staining was performed using myofibroblast markers such as α-SMA and SM22 to confirm the presence or absence of myofibroblasts.

[0183] <Monograph>

[0184] Definition of terms

[0185] 1. "Wound"

[0186] In this specification, the term "wound" means damage to any tissue (including, for example, acute, subacute, delayed, or difficult-to-heal wounds, and chronic wounds). Also, "wounds" can include open wounds and closed wounds. Tissues where wounds can occur can include skin and subcutaneous tissue, muscle tissue, peritoneum, digestive organs, digestive tract, etc.

[0187] The healing process of a "wound" is generally broken down into four steps: a hemostasis phase, an inflammation phase, a proliferation phase, and a tissue remodeling phase. In the proliferation phase, myofibroblasts and capillaries invade the wound site, promoting the proliferation of myofibroblasts and the production of collagen. As a result, granulation tissue is formed at the wound site during the proliferation phase. The abundant blood vessels in the granulation tissue formed during the proliferation phase will eventually regress during the subsequent tissue remodeling phase and are ultimately replaced by scar tissue mainly composed of collagen. It is known that excessive deposition of collagen during a series of wound healing processes can form hypertrophic scars and keloids.

[0188] Here, when classifying wounds into defective wounds and non-defective wounds and specifically explaining the wound healing process individually, both defective wounds and non-defective wounds experience the hemostasis phase, inflammation phase, proliferation phase, and tissue remodeling phase in sequence. Among them, defective wounds have tissue defect parts to be filled during the inflammation phase and proliferation phase, while non-defective wounds do not have tissue defect parts to be filled during the inflammation phase and proliferation phase.

[0189] Therefore, regarding defective wounds, whether for the purpose of suppressing scarring, if a scaffold material containing an anti-fibrotic agent is administered into the wound at the initial stage of the wound healing process, there is a risk of delaying wound healing. In contrast, for non-defective wounds, even if a scaffold material containing an anti-fibrotic agent is administered into the wound at the initial stage of the wound healing process, there is no risk or at least less risk of delaying wound healing.

[0190] Based on this finding, the inventor has devised a technique of placing the scaffold material into a non-defective wound at the initial stage of its healing process when the object to be healed is a non-defective wound.

[0191] 2. "Scar", "Suppression of scarring", etc.

[0192] In this specification, the term "scar" means fibrous connective tissue formed at the damaged site of any body tissue. Scar tissue is typically composed of the same protein (i.e., collagen) as the replaced tissue. However, the fiber composition of scar tissue is significantly different from that of scar-free tissue. Types of scars may include, but are not limited to, atrophic scars, skin graft scars, hypertrophic scars, keloids, etc. Also, scar sites may include, but are not limited to, scars on the skin and subcutaneous tissue, scars on the peritoneum, abdominal cavity and intra-abdominal organs, scars on muscles, tendons or joints, etc.

[0193] As used herein, the term "hypertrophic scar" means a raised scar formed by the excessive production of extracellular matrix (ECM) that attempts to repair a wound (hereinafter sometimes referred to as the "wound site") after trauma. Among hypertrophic scars, those that spread to normal skin are particularly called "keloids".

[0194] As used herein, "scarring (also referred to as "scar formation")" refers to the replacement of a damaged site of living tissue by ECM (mainly collagen).

[0195] In the case of a wound to the human body surface, except for minor exceptions such as the fingertips, injuries that do not reach deeper than the outer layer of the skin (dermal papillary layer) result in little or no scarring (i.e., regeneration). However, when an injury reaches the reticular layer of the dermis, the tissue is reconstructed and healed with scarring (i.e., scar healing).

[0196] As used herein, the terms "inhibition of scarring", "inhibition of scar formation", "anti-scarring", and "inhibit the formation of scars" mean inhibiting the excessive growth of granulation tissue or the excessive production of collagen during the proliferation phase and tissue remodeling phase of the wound healing process.

[0197] 3. "Treatment"

[0198] As used herein, the term "treatment" includes not only the treatment in the ordinary sense that is performed on a patient after the onset of the target disease, but also curing, improving, or at least partially improving the disorder, and also includes preventive measures that are performed in advance to prevent the occurrence and recurrence of hypertrophic scars and / or keloids.

[0199] 4. "Extracellular Matrix (ECM)"

[0200] As used herein, the term "extracellular matrix (ECM)" refers to something that has a role in governing the organization of cells in a living body. The ECM serves as a structural scaffold for cells and is a major part as physical support in the formation of tissues, organs, and viscera. The ECM is mainly composed of three major classes of biomolecules including fibrous proteins such as collagen (e.g., type I, type III) and elastin, glycoproteins such as fibrillin, fibronectin, and laminin, and proteoglycan complexes such as aggrecan and versican.

[0201] 5. "Collagen"

[0202] As used herein, the term "collagen" refers to an abundant protein present in the ECM.

[0203] 6. "Fibrosis"

[0204] As used herein, the term "fibrosis" means the deposition of ECM proteins (mainly collagen) in the tissues of a living body.

[0205] 7. "Antifibrosis" etc.

[0206] As used herein, the terms "antifibrosis", "fibrosis suppression", and "fibrosis inhibition" mean suppressing the progression of fibrosis in a tissue.

[0207] 8. "Antifibrotic agent" etc.

[0208] As used herein, the terms "antifibrotic agent", "fibrosis suppressant", or "fibrosis inhibitor" mean a medicament having a prophylactic or therapeutic effect against fibrosis in a tissue. For example, an antifibrotic agent prevents or treats fibrosis by suppressing the differentiation of fibroblasts into myofibroblasts.

[0209] In addition, anti-fibrotic agents can be classified according to the difference in molecular weight into those with a small molecular weight (with a molecular weight of about 300 - about 400, such as pirfenidone, etc.) and those with a large molecular weight (with a molecular weight of about 36,000 - about 40,000, such as decorin, etc.).

[0210] 9. "Biomaterial"

[0211] In this specification, the term "biomaterial" means a product having a specific use and a specific function, different from the broad sense of the term "biomaterial" which simply means a specific material.

[0212] Specifically, in this embodiment, the "biomaterial" is produced using a natural or synthetic biocompatible material that maintains selected bioactive cells in a viable state and is suitable for introduction into a living tissue.

[0213] Furthermore, in this embodiment, the "biomaterial" is produced using a material among the biocompatible materials that functions as an artificial ECM serving as a scaffold for the progenitor cells and is suitable for supporting the proliferation of the progenitor cells.

[0214] By the way, as the biocompatible material, there are an in-vivo retention type that is retained in the living body after introduction into the living tissue and an in-vivo degradation type that is decomposed and absorbed in the living body after introduction into the living tissue. However, in this embodiment, the "biomaterial" is produced using an in-vivo degradation type biocompatible material. Therefore, the "biomaterial" is of the in-vivo degradation type and is replaced by self-tissue over time, and as a result, disappears in the body.

[0215] 10. "Scaffold" and "scaffold material"

[0216] In this specification, the term "scaffold" is defined as, for example, realizing a function of securing a space for tissue regeneration, assisting the regeneration of damaged tissue while maintaining the shape of the regenerated tissue. Also, the term may be defined as, for example, realizing a function of three-dimensionally distributing target cells, providing a space for the regeneration of target cells while imparting a specific shape.

[0217] An actual substance or object administered into the body to realize this "scaffold" function is an artificial "scaffold material". Thus, in the present embodiment, the "scaffold material" has, for example, good adhesiveness to target cells (for example, the progenitor cells), biocompatibility or biocompatibility as a property that does not have an adverse effect on the living body, low immunogenicity, and is easily absorbed by the living body after becoming unnecessary after being implanted in the body, and has sufficient strength not to be damaged even when the body moves.

[0218] Next, the several embodiments will be individually described.

[0219] <First Embodiment>

[0220] 1. Configuration of Scaffold Material

[0221] (1) Selection of Anti-Fibrotic Agent

[0222] As two options for the anti-fibrotic agent, both Ripasudil hydrochloride hydrate (Ripasudil) and Fasudil hydrochloride hydrate (Fasudil), which are both commercially available drugs, were selected. Both Ripasudil and Fasudil are classified as ROCK inhibitors. All of these anti-fibrotic agents are in liquid form.

[0223] (2) Selection of Biomaterial

[0224] As a biomaterial for a biological scaffold material, a gelatin hydrogel (Genocel (registered trademark)) was selected. The agent named Genocel (registered trademark) is manufactured by Kyoto Medical Design Co., Ltd. and is a cell culture scaffold material using gelatin with a non-woven structure.

[0225] This gelatin hydrogel comes in sheet type, block type, and powder type. The biomaterial used for the scaffold material according to this embodiment is of the powder type and is configured as a powder agent, that is, a powder. Therefore, this biomaterial is a solid agent.

[0226] 2. Manufacturing method of the scaffold material

[0227] (1) Two-component mixing type

[0228] The scaffold material according to this embodiment is of type 1 in FIG. 5 and is manufactured by mixing a powdery biomaterial and a liquid anti-fibrotic agent.

[0229] (2) On-site manufacturing type

[0230] To manufacture the scaffold material, the biomaterial and the anti-fibrotic agent are mixed at the site where the anti-scar treatment is performed (for example, in the operating room).

[0231] The mixing process is carried out in the two-component mixing type injector shown in FIG. 3.

[0232] Specifically, the injector has a main body portion with two chambers and a nozzle located at the tip of the main body portion. This injector further has a switching function that always keeps the two chambers in an isolated state but switches them to a communicating state when an external force acts. Before mixing, the biomaterial and the anti-fibrotic agent are separately and isolatedly accommodated in the two chambers.

[0233] At the site where the anti-scarring treatment is performed, when the external force acts for mixing, the two chambers are communicated with each other, whereby the mixing is started. Thereafter, when the same first external force as the external force for mixing or a different second external force acts for mixing, the scaffold material moves from the accommodating portion to the nozzle, and the required amount of the scaffold material is discharged from the nozzle.

[0234] Note that the injector has a mixing function for mixing the two agents in addition to the injection function for injecting the mixed solution. Instead, an injector of a type that has an injection function but does not have a mixing function may be used. In that case, prior to the use of the injector, an operator may mix the two agents at the site or at a different location, and further fill the injector with the mixed solution thus prepared.

[0235] 3. Administration method of the scaffold material

[0236] Liquid injection type

[0237] The scaffold material is configured as a liquid injection agent that is injected into the gap between the wound surfaces facing each other in the wound.

[0238] The scaffold material is locally administered, for example, intradermally, to the wound at the site where the anti-scarring treatment is performed. The scaffold material is administered to the wound at the initial stage of the wound healing process, for example, immediately after suturing, within 5 minutes after the end of suturing, etc. The administration may be performed after the end of suturing for the entire wound, or may be performed in parallel with the progress of suturing.

[0239] As shown in FIGS. 6 and 7, a wound as an incision wound is sutured with sutures or staples, and in some cases, is closed and fixed without sutures (closed wound). For the incision wound, dermal suture and epidermal suture, or either one of them, is performed. Dermal suture is a suture method in which the first layer of epidermis of the skin is not penetrated and the suture needle is passed through the second layer of dermis for suturing. Epidermal suture is a general term for various suture methods that penetrate the first layer of epidermis for suturing. Here, the "incision wound" is referred to as the "skin suture wound" as described above when it is in a sutured state. Also, the "incision wound" is a surgical wound and is a non-defective wound.

[0240] After suturing, the scaffold material is locally administered into the wound. As shown in FIGS. 6 and 7, the scaffold material is injected into the wound with the nozzle of the injector inserted into the wound gap using the injector. Alternatively, the scaffold material can be injected into the wound using, for example, a needle or a needleless device, or a syringe, a bottle, a dropper, a pipette, etc. As is apparent from the first and second figures from the right in FIG. 7, the scaffold material is placed at a position isolated from the epidermis or epithelium shown in FIG. 2.

[0241] The scaffold material is injected into at least one of a plurality of regions partitioned by a plurality of sutures in a wound of the sutured wound that extends in the axial direction for each region. The scaffold material can be successively injected into those regions in the direction in which they are arranged, or injected one by one or at intervals.

[0242] For convenience of explanation, as exaggeratedly shown in FIG. 7, the scaffold material is injected into the wound gap. Since the scaffold material has bioabsorbability, it will eventually be replaced by autologous tissue and disappear.

[0243] 4. Mechanism of action of anti-scarring using a scaffold material containing an anti-fibrotic agent

[0244] As shown in FIG. 2, when the scaffold material is administered into the wound, fibroblasts in the living tissue move toward the scaffold material.

[0245] The fibroblast adheres to the scaffold material, and accordingly, the fibroblast reacts with the anti-fibrotic agent in the scaffold material. Thereby, the differentiation of fibroblasts into myofibroblasts, and thus the increase in myofibroblasts, is suppressed. As a result, the production of collagen from myofibroblasts is suppressed, thereby inhibiting excessive scarring of biological tissues during the wound healing process. Thereafter, the biomaterial decomposes and disappears.

[0246] Specifically, when the scaffold material is implanted into the living body, the scaffold material defines a space isolated from the surrounding tissue of the wound in the living body, and the progenitor cells can enter into the space. When the progenitor cells enter into the space, the entered progenitor cells react with the anti-fibrotic agent present in the scaffold material. Thereby, the transformation of the progenitor cells into myofibroblasts is inhibited, and thereby, an anti-scarring treatment is performed.

[0247] Furthermore, the scaffold material has a function of defining an administration route of the anti-fibrotic agent in the living body, a function of providing a scaffold for progenitor cells from outside the living body, and a function of supplementing the wound from outside the living body with an artificial ECM as a substitute for the original ECM severed by the wound.

[0248] 5. Experimental method

[0249] Under the above-mentioned basic policy, in order to confirm the effectiveness of the scaffold material according to this embodiment in relation to the anti-scarring treatment in the wound healing process of the skin of a living body, an experiment was conducted.

[0250] The purpose of this experiment is to evaluate the effectiveness of the scaffold material using a model animal. Specifically, an incision wound model of 8-week-old mice was used to evaluate the scarring inhibitory effect during the wound healing process.

[0251] 5-1. Animals used in the experiment

[0252] As experimental animals, 12 male C57BL / 6JJcl strain mice (8 weeks old, Japan CLEA Inc.) were used. The mice were housed in groups of three per cage using clean S cages and mouse M2 cages, and were bred in a standard environment (temperature: 20°C - 26°C, humidity: 40% - 70%, 12-hour light-dark cycle). Food and water were provided ad libitum. After the procedures described below, the mice were housed individually in separate cages to prevent other individuals from damaging the wounds.

[0253] 5-2. Grouping of Multiple Mice

[0254] The 12 mice were randomly divided into four groups as shown in tabular form in Figure 8: Control group 1 (n = 3), Control group 2 (n = 3), Treatment group 1 (n = 3), and Treatment group 2 (n = 3).

[0255] 5-3. Treatments for Mice

[0256] Each mouse was anesthetized by inhaling an anesthetic (e.g., isoflurane inhalation anesthetic "VTRS" (manufactured by ViaTris Pharmaceutical Co., Ltd.)). Furthermore, the back of each mouse was shaved. Additionally, the skin at the incision site on the back of each mouse was disinfected with a disinfectant (e.g., povidone-iodine gel).

[0257] Furthermore, two discrete incisions approximately 10 mm in length and full-thickness of the skin were made longitudinally (in the body length direction) on each mouse. Subsequently, each incision on each mouse was sutured epidermally with two stitches per incision using a suture (e.g., 6-0 nylon suture). Here, an "incision wound" is a surgical wound and thus a non-defective wound.

[0258] In each mouse, two wound sites were formed. Scar tissue was collected from one wound site on the third day after surgery, and scar tissue was collected from the other wound site on the seventh day after surgery.

[0259] 5-4. Setting of Control Groups

[0260] As two types of control groups, as shown in tabular form in Fig. 8, Control group 1: A group in which the wound was simply sutured without administering either the biomaterial or the antifibrotic agent, Control group 2: A group in which purified water was added to a biomaterial not containing an antifibrotic agent, and the resulting material was administered into the wound as a gel-like scaffold were set up.

[0261] In each control group, three mice were used. The individual numbers 101, 102, and 103 of the three mice in control group 1 and the individual numbers 201, 202, and 203 of the three mice in control group 2 are shown in the figure.

[0262] For control groups 1 and 2, more specifically, it is as follows.

[0263] Administration group: Control group 1 Dosage of antifibrotic agent: 0 Dosage volume of scaffold material: 0 Administration group: Control group 2 Dosage of antifibrotic agent: 0 Dosage volume of scaffold material: 20 μL / wound site (20 μL was administered to each of the two wound sites of each mouse.) (That is, a total of 20 μL of the scaffold material was administered to each wound site so as to be approximately evenly distributed among the following three regions, i.e., the administration positions. This also applies to other groups.) Preparation method: 200 μL of purified water was added to 800 μg of Genocel (registered trademark) powder using a 200 μL pipette tip, and the mixture was suspended by pipetting or inversion mixing. Administration was carried out immediately after the preparation.

[0264] 5 - 5. Setting of treatment groups

[0265] As two types of treatment groups, as shown in tabular form in Fig. 8, Treatment group 1: A group in which fasudil was contained in the biomaterial and the resulting material was administered into the wound as a gel-like scaffold Treatment group 2: A gel scaffold containing lipasudil in the biomaterial was administered into the wound was set up.

[0266] In each treatment group, three mice were used. The individual numbers of the three mice in treatment group 1, 301, 302, and 303, and the individual numbers of the three mice in treatment group 2, 401, 402, and 403, are shown in the figure.

[0267] For treatment groups 1 and 2, more specifically, it is as follows.

[0268] Administration group: Treatment group 1 Administration concentration of the antifibrotic agent: 30 mg / mL Administration volume of the scaffold: 20 μL / wound site (20 μL was administered to each of the two wound sites of each mouse.) Dosage of the scaffold: Approximately 53.1 mg / kg (weight per kg of each mouse of the scaffold administered to each mouse) Preparation method: Using a 200 μL pipette tip, 200 μL of fasudil (30 mg of Eril (registered trademark) intravenous drip solution) was added to 800 μg of Genocel (registered trademark) powder, and it was suspended by pipetting or inverting and mixing. Administration was carried out immediately after its preparation.

[0269] Administration group: Treatment group 2 Administration concentration of the antifibrotic agent: 4 mg / mL Administration volume of the scaffold: 20 μL / wound site (20 μL is administered to each of the two wound sites of each mouse) Dosage of the scaffold: Approximately 7.1 mg / kg (weight per kg of each mouse of the scaffold administered to each mouse) Preparation method: Using a 200 μL pipette tip, 200 μL of lipasudil (0.4% of Granatic (registered trademark) eye drops) was added to 800 μg of Genocel (registered trademark) powder, and it was suspended by pipetting or inverting and mixing. Administration was carried out immediately after its preparation.

[0270] In Treatment Group 1, the concentration of fasudil was 30 mg / mL, but in the scaffold material according to this embodiment, the concentration of fasudil can be, for example, within the range of about 28 mg / mL to about 32 mg / mL, or within the range of about 25 mg / mL to about 35 mg / mL, or within the range of about 20 mg / mL to about 40 mg / mL.

[0271] Similarly, in Treatment Group 2, the concentration of ripasudil was 4 mg / mL, but in the scaffold material according to this embodiment, the concentration of ripasudil can be, for example, within the range of about 3.5 mg / mL to about 4.5 mg / mL, or within the range of about 3 mg / mL to about 5 mg / mL, or within the range of about 2.5 mg / mL to about 5.5 mg / mL.

[0272] 5 - 6. Administration Method

[0273] For Control Group 2, immediately after the production of the scaffold material (without an antifibrotic agent), the scaffold material was administered to each mouse. Also, for Treatment Groups 1 and 2, immediately after the production of the scaffold material (with an antifibrotic agent), the scaffold material was administered to each mouse.

[0274] Specifically, as shown in FIG. 9, for the mice in Control Group 2, Treatment Group 1, and Treatment Group 2 after the suture treatment, under anesthesia, 20 μL of the scaffold material was evenly administered into the wound by using a 200 μL pipette tip to three regions created by suturing each incision (each wound site) at two locations.

[0275] Therefore, a total of 20 μL of the scaffold material was administered per wound site. The scaffold material was locally administered, using the pipette tip, to a position isolated from the epithelium in the internal space (gap) of each wound site as described above with reference to FIG. 7. After administration, each mouse was kept warm with a warming mat. After confirming that each mouse had awakened from anesthesia, an analgesic (carprofen) was allowed to be freely ingested.

[0276] 6. Experimental Results

[0277] 6-1. Observation of the Wound Site

[0278] Taking the day of surgery (wound creation) as day 0, the wound sites of each mouse on day 0, day 3, and day 7 were photographed with a scale. Among the photographed images, those on day 3 (Day 3) are shown in Figure 10, and those on day 7 (Day 7) are shown in Figure 11, respectively.

[0279] In each figure, the label "Sham" means control group 1, the label "Genocel (registered trademark)" means control group 2, the label "Genocel (registered trademark) + Fasudil" means treatment group 1, and the label "Genocel (registered trademark) + Ripasudil" means treatment group 2.

[0280] Furthermore, in each figure, the label "HE" means a micrograph of a specimen stained with hematoxylin and eosin (hereinafter referred to as "HE staining"), and the label "α-SMA" means a micrograph of a specimen stained immunohistochemically with an anti-α-SMA antibody (or referred to as "α-SMA immunostaining").

[0281] Figure 12 shows in tabular form whether the wound sites of each group were epithelialized on day 3 and day 7. Here, "epithelialization" means that the epithelium of the wound site is completely continuous and the wound has healed.

[0282] 6-2. Staining

[0283] On day 3 and day 7, the scar (scar tissue) was excised from the wound site of each mouse, and HE staining and α-SMA immunostaining were performed on it.

[0284] Specifically, the following multiple operations were performed in sequence.

[0285] (1) For each mouse, on the 3rd and 7th days, after observing each wound site, anesthesia was induced by inhalation of the isoflurane anesthetic "VTRS" (manufactured by ViaPharma Co., Ltd.).

[0286] (2) After removing the sutures in each mouse, for each wound site, a portion having a size of about 15 mm in major axis and a drop shape (for example, a plate-like portion generally circular or elliptical in plan view) was cut out from the skin of each mouse so that each wound site was located approximately at the center, and the cut-out portion was trimmed into a rectangular shape to prepare a scar specimen.

[0287] (3) After thus removing the scar specimens for each wound site from each mouse, in each mouse, the skin was sutured for each wound site, and each mouse was allowed to freely ingest an analgesic (carprofen) in drinking water.

[0288] (4) Each excised scar specimen was fixed with formalin and then embedded in paraffin.

[0289] (5) A plurality of sections were cut out from each paraffin-embedded scar specimen, and each section was prepared as a paraffin section.

[0290] (6) The first subset of the plurality of paraffin sections was stained with HE, and the second subset was subjected to immunohistochemical staining (hereinafter also referred to as "α-SAM immunostaining") using an anti-α-SMA antibody (M0858, 1:300, Dako).

[0291] For each paraffin-embedded scar specimen, one HE-stained specimen and one α-SMA immunostained specimen were prepared as tissue staining samples, respectively.

[0292] 6-3. Evaluation of scar formation expression

[0293] (1) Measurement of scar cross-sectional area

[0294] For each group, three HE-stained specimens on the 7th day were observed and photographed under an optical microscope. In each micrograph, the boundary between the scarred area and the non-scarred area where scarring occurred was traced on NDP.view2 software (Hamamatsu Photonics K.K.), and the area of the enclosed scarred area was quantified as the scar cross-sectional area.

[0295] Figures 13 - 16 show micrographs of one HE-stained specimen on the 7th day for control groups 1 and 2 and treatment groups 1 and 2, respectively.

[0296] In the micrographs shown in each figure, the boundary line between the scarred area and the other area was extracted as a single closed line by focusing on the difference in the properties of collagen fibers. Specifically, in the dermis layer, an area with a large number of cells, dense collagen fibers, and randomly arranged collagen fiber bundles was distinguished from other areas and determined to be the scarred area.

[0297] In the micrographs shown in each figure, a line is added for the purpose of facilitating explanation to highlight the boundary line of the scarred area extracted as described above.

[0298] Figure 17 shows the four boundary lines extracted as described above for the four groups arranged in a horizontal row in order.

[0299] Figure 18 shows in tabular form the scar cross-sectional areas calculated for the corresponding scarred areas for each group and for each mouse. The figure also shows in tabular form the average values of the scar cross-sectional areas for each group.

[0300] (2) Significance of experimental data

[0301] To evaluate the statistical reliability and significance of multiple scar cross-sectional areas as experimental data, one-way ANOVA was performed using GraphPad Prism 9 (GraphPad Software, LLC), followed by Tukey's test, and the experimental data were statistically analyzed based on the results of these tests. The results are shown in tabular form in Figures 19 - 22.

[0302] Specifically, Figure 19 shows the ANOVA test results (labeled "ANOVA Results") in tabular form.

[0303] Also, Figure 20 shows multiple comparisons (labeled "Multiple Comparisons (Tukey's test results)") in tabular form.

[0304] Also, Figure 21 shows descriptive statistics (labeled "Descriptive Statistics") for multiple standard statistical values related to the experimental data used in the ANOVA test and multiple comparisons in tabular form.

[0305] Also, Figure 22 shows the mean and standard deviation of the scar cross-sectional area of each group in a graph, and further shows that there is a significant difference in the scar cross-sectional area between control group 2 and treatment group 2. (P = 0.03)

[0306] In these figures, the definitions of the main symbols among the multiple symbols are as follows.

[0307] A: Control group 1 B: Control group 2 C: Treatment group 1 D: Treatment group 2 ns: No significant difference *: Significant difference SS: sum of squares, variation DF: degrees of freedom MS: mean square SD: Standard deviation F: F value Cl: Confidence interval P-value: P value

[0308] When P < 0.05 holds for the difference between groups of experimental data, the difference between the groups is statistically significant, and it was determined that there is a significant difference between the compared groups.

[0309] (3) Evaluation of the amount of myofibroblasts

[0310] On the 3rd and 7th days after α-SMA immunostaining, each section was observed and photographed under a microscope, and the presence or absence of myofibroblasts was visually evaluated from the images of each micrograph. The micrographs of each section on the 3rd day are shown in Fig. 10, and the micrographs of each section on the 7th day are shown in Fig. 11.

[0311] 6-4. Results and discussion

[0312] (1) Visual inspection of the wound site

[0313] On the 3rd day in mice, the wound sites did not epithelialize in any group. In contrast, on the 7th day in mice, the wound sites epithelialized in all groups.

[0314] (2) Statistical analysis

[0315] a. Efficacy of lipasdil as an antifibrotic agent

[0316] As shown in Figs. 20 and 22, the treated group 2 showed a decrease in the scar cross-sectional area compared to the control group 2, and there was a significant difference between the two statistically (p = 0.03).

[0317] From this, it was considered that lipasdil among the scaffolds according to this embodiment has an anti-scarring effect alone.

[0318] b. Possibility of fasdil as an antifibrotic agent

[0319] As shown in Figs. 20 and 22, the treated group 1 showed a decrease in the scar cross-sectional area compared to the control group 2.

[0320] In this case, although there was no significant difference statistically between the two, it was considered that Faszil among the scaffold materials according to this embodiment might have an anti-scarring effect alone.

[0321] In addition, in Treatment Group 1, if the concentration and / or dosage of Faszil had been set higher than the experimental values this time, it is presumed that the anti-scarring effect for this Treatment Group 1 would have been increased compared to that shown in FIG. 22.

[0322] Also, when using Faszil at the same concentration and dosage as in this experiment in Treatment Group 1 and treating a larger number of individuals, there is also a possibility that the scar area will be significantly reduced compared to Control Group 2.

[0323] Therefore, it is determined that not only Lipaszil but also Faszil can exert an anti-scarring effect in the presence of a biomaterial as an anti-fibrotic agent.

[0324] c. Significance of the presence of biomaterial

[0325] As shown in FIGS. 20 and 22, Control Group 2 was larger than Control Group 1 with respect to the scar cross-sectional area.

[0326] The reason for this is that in Control Group 2, since a biomaterial not containing an anti-fibrotic agent was placed in the gap of the suture wound, the biomaterial functioned as a space where myofibroblasts could adhere, and active collagen production by myofibroblasts was carried out inside, so it was determined that the scar cross-sectional area was larger than that of Control Group 1.

[0327] On the other hand, in Treatment Group 1 and Treatment Group 2, since the scar cross-sectional area was not larger than that of Control Group 1, it can be determined that the anti-fibrotic agent functioned sufficiently and collagen production was suppressed.

[0328] (3) Naked-eye view of microscopic photographs of HE-stained specimens

[0329] Macroscopic observation of the microscopic photographs of the HE-stained specimens revealed that, as shown in FIGS. 13 to 16, on the 7th day in mice, scar tissue was confirmed at the wound site in all groups.

[0330] Furthermore, as shown in FIG. 17, Treatment Groups 1 and 2 were smaller than Control Groups 1 and 2 with respect to the scar cross-sectional area.

[0331] From these results, it was considered that lipasudil and fasudil as antifibrotic agents have an anti-scarring effect.

[0332] (4) Macroscopic observation of the microscopic photographs of the α-SMA immunostained specimens

[0333] Macroscopic observation of the microscopic photographs of the α-SMA immunostained specimens showed that, as shown in FIG. 11, scar tissue containing myofibroblasts was formed at the wound, which was confirmed.

[0334] Furthermore, as shown in the same figure, Treatment Groups 1 and 2 had fewer α-SMA-positive myofibroblasts than Control Groups 1 and 2.

[0335] Control Group 2 had more myofibroblasts than Control Group 1. The reason for this has been described above.

[0336] 6-5. Supplementary

[0337] The results and discussions of the above experiments indicate that the scaffold material according to this embodiment has a scarring inhibitory effect. Although this experiment was conducted on the skin of mice, based on common technical knowledge and experience, it is considered that if the same kind of experiment is conducted on human skin, the same mechanism of action and effects can be obtained.

[0338] 7. Effects

[0339] (1) Measures against delayed wound healing as a side effect due to scarring inhibition

[0340] According to the present embodiment, in the process of natural healing of a deep wound (for example, a surgical wound) where the wound surface reaches the subcutaneous tissue without tissue defect, scarring of the tissue is suppressed, so it becomes easy to liberate the patient from inconveniences such as functional disorders, pain, and mental distress caused by scars.

[0341] By the way, in the present embodiment, since scarring of the tissue is suppressed during the wound healing process, there is a possibility that wound healing may be delayed. However, in the scaffold material, the biomaterial has a function of assisting the migration and adhesion of the progenitor cells such as fibroblasts in the living body.

[0342] Therefore, according to the present embodiment, unless early wound healing is particularly strongly desired due to tissue defect, it is expected that epithelialization will not be delayed due to the delayed healing caused by scarring suppression. This was verified by the fact that epithelialization was obtained in all treatment groups on Day 7 of the experimental results (see Fig. 12).

[0343] That is, according to the present embodiment, it is possible to consider that the scaffold material has two base agents having effects antagonistic to each other, namely, an anti-fibrotic agent that suppresses tissue scarring in the wound healing process and delays wound healing as a secondary effect, and a biomaterial that attenuates the wound healing delay effect by assisting the migration and adhesion of the progenitor cells.

[0344] Therefore, according to the present embodiment, it goes without saying that the delay in wound healing can be attenuated by adjusting the concentration (concentration and dilution) and / or dosage (increase and decrease) of the anti-fibrotic agent. Instead, it can be attenuated by adjusting the concentration and / or dosage of the biomaterial. In addition to the above adjustment, it can also be attenuated by adjusting the concentration and / or dosage of the biomaterial.

[0345] As a result, according to the present embodiment, there are plural prescription options that an operator can adopt to reduce the wound healing delay effect that occurs as a side effect, and thereby, it becomes easy to select and optimize the plural options in an individualized manner according to the characteristics of the patient and the wound.

[0346] (2) Simplification of procurement of the scaffold material

[0347] According to the present embodiment, a plurality of types of commercially available pharmaceuticals for which safety and efficacy have been established for other uses can be diverted to a biomaterial and an antifibrotic agent as the main components of the scaffold material, respectively, and can be procured by simply mixing the two.

[0348] Therefore, according to the present embodiment, it becomes easy to procure a scaffold material for performing an anti-scarring treatment in the wound healing process simply, at low cost, and safely.

[0349] (3) High permeability by a low molecular weight antifibrotic agent

[0350] According to the wound scaffold material according to the present embodiment, a relatively low molecular weight antifibrotic agent such that the molecular weight is 400 or less is used. Therefore, such a low molecular weight antifibrotic agent is chemically synthesized at low cost and easily as compared with a high molecular weight antifibrotic agent such that the molecular weight is 10,000 or more, and in addition to the stable structure, since such a low molecular weight antifibrotic agent acts inside cells, it is possible to directly and effectively suppress the signal transduction pathway from the progenitor cells to myofibroblasts.

[0351] (4) Long-term preservability of the drug

[0352] According to the present embodiment, prior to the intracerebral administration of the scaffold material using the injector shown in FIG. 3, the biomaterial and the antifibrotic agent are stored as solid agents instead of liquid agents, for example, in a storage place or in the injector. Therefore, according to the present embodiment, deterioration of the drug is suppressed as compared with the case where the biomaterial is a liquid agent, and long-term storage of the drug becomes easy.

[0353] (5) Improvement in quality stability of the scaffold material

[0354] According to the present embodiment, at the site where the anti-scar treatment is performed, at the stage where the treatment is about to be performed, an operator or an assistant can prepare the scaffold material by mixing the biomaterial and the antifibrotic agent using an injector. Therefore, even if there is a possibility that some denaturation may occur in the mixed solution after the mixing, the period during which such a possibility exists can be shortened.

[0355] As a result, according to the present embodiment, it becomes easy to use the scaffold material with desired performance, and the quality stability of the scaffold material is improved.

[0356] (6) Possibility of application to the field of aesthetic medicine

[0357] According to the wound scaffold material according to the present embodiment, the occurrence of scars and post-wound marks can be suppressed or prevented. Therefore, the wound scaffold material according to the present embodiment can be applied not only to the medical field associated with disease treatment but also to the field of plastic surgery.

[0358] <Second Embodiment>

[0359] In the present embodiment, as a specific example of the two-component mixing type injector shown in FIG. 3, the injector 10 shown in FIG. 23 is used.

[0360] 1. Configuration

[0361] As shown in the figure, this injector 10 has a main body 30 having a front end and a rear end, and a first chamber 20 on the front end side and a second chamber 22 on the rear end side. Before the preparation of the scaffold material (mixed solution) 100, that is, before the mixing of the biomaterial (powder agent) 102 and the antifibrotic agent (liquid agent) 104, the biomaterial 102 and the antifibrotic agent 104 are separately accommodated as drugs in the first and second chambers 20 and 22, respectively. The biomaterial 102 and the antifibrotic agent 104 may be accommodated in any of the chambers 20 and 22.

[0362] In the example shown in the figure, the powdery biomaterial 102 is accommodated in the first chamber 20 in the presence of air. Further, in the example shown in the figure, the second chamber 22 is formed in a glass ampoule, and a liquid or gel-like antifibrotic agent 104 is encapsulated in the ampoule.

[0363] The nozzle 40 extends from the tip of the tip side portion 60. The tip side portion 60 has the property of being at least partially flexible. Further, the nozzle 40 has the property of being at least partially flexible. The cross-sectional shape of the nozzle 40 may be circular or flat. When the nozzle 40 has a flattened cross-sectional shape, the moving resistance may be reduced when moving it in the longitudinal direction within a narrow wound gap, and the convenience may be improved. At the tip of this nozzle 40, the discharge port of the scaffold material 100 (mixed liquid) is opened.

[0364] The main body portion 30 is divided into two parts, a tip side portion 60 forming the first chamber 20 and a rear end side portion 62 forming the second chamber 22, and the two are connected to be relatively rotatable at the end portions facing each other.

[0365] This injector 10 further always maintains the first and second chambers 20 and 22 in an isolated state without breaking the diaphragm function portion 70 that functions as a diaphragm (or partition wall) between the first and second chambers 20 and 22. However, when a relative rotational force is applied to the tip side portion 60 and the rear end side portion 62 and they rotate relative to each other, the diaphragm function portion 70 is broken, and it has a selective communication mechanism 72 that communicates the first and second chambers 20 and 22 with each other.

[0366] This selective communication mechanism 72 includes, for example, a screw mechanism that converts the relative rotational force into an axial force acting in the axial direction of the injector 10, and an engaging protrusion that is moved in the axial direction by the axial force. It is possible to be configured to break the diaphragm function portion 70 having a portion extending in a direction intersecting the axial direction by engaging with the engaging protrusion.

[0367] An example of the diaphragm functional part 70 is a part of the wall of the glass ampoule. When a part of the wall engages with the engaging projection (a rigid body such as metal), it breaks, and then the broken part functions as a passage that allows the anti-fibrotic agent 104 to move from the second chamber 22 to the first chamber 20.

[0368] 2. Operation

[0369] In the communicating state of the first and second chambers 20 and 22, for example, the anti-fibrotic agent in the second chamber 22 flows into the first chamber 20, and in the first chamber 20, the flowed-in anti-fibrotic agent and the powdery biomaterial that originally existed are mixed to form a single liquid agent. In this state, the operator shakes the injector 10 or the like to stir the mixed liquid and uniformly mix the two agents.

[0370] During the process of mixing and stirring (for example, in the standby state), in order to prevent the scaffold material in the injector 10 from leaking from the nozzle 40 against the will of the operator, for example, a locking member 80 that can selectively perform at least locally blocking the nozzle 40 may be used. The locking member 80 is, for example, an elastic clip in which a pair of arms are elastically connected to each other at a hinge.

[0371] 3. Effect

[0372] Thanks to the characteristic that the tip side part 60 is at least partially flexible, when there is a scaffold material as a mixed liquid in the first chamber 20, the operator can press the tip side part 60 to reduce the volume of the first chamber 20, so that the scaffold material can be discharged from the nozzle 40 in a required amount according to the pressing force.

[0373] Thanks to the characteristic that the nozzle 40 is at least partially flexible, when the operator injects the scaffold material into the wound, for example, when the nozzle 40 is inserted into the wound gap, if the nozzle 40 tries to tilt with respect to the wound surface, it is easy to maintain a state of following the wound surface without gaps and without applying excessive force to the wound surface.

[0374] <Some other embodiments>

[0375] In some of the preceding embodiments, the biomaterial has a powder dosage form, but alternatively, it may be in the form of a hydrogel or a sponge, and instead of the dosage form of a dispersant, it may have a continuous form, for example, in the form of a film or a sheet (for example, with or without flexibility). Further, the biomaterial may be in the form of a sheet in which the material is processed to have a specific shape (for example, an outer shape, an overall shape, a three-dimensional shape, a shape having holes penetrating in the thickness direction, a porous shape, etc.), for example, in the form of a mesh sheet.

[0376] In some of the preceding embodiments, the scaffold material is configured to hold an anti-fibrotic agent at least until it is placed from outside the body into the body (for example, until it moves from outside the body into the body), but it may also be configured to hold the anti-fibrotic agent over a longer period, for example, while it is placed in the body (until the scaffold material is absorbed and decomposed and disappears). Just to be on the safe side, the scaffold material is configured to function as a holder, for example, as an object that holds the anti-fibrotic agent.

[0377] In some of the preceding embodiments, fibroblasts were considered as the progenitor cells, but alternatively or in addition, mesothelial cells may also be considered.

[0378] Furthermore, as the progenitor cells, in addition to fibroblasts or mesothelial cells, a cell population including at least one of mesenchymal stem cells, bone marrow-derived stem cells, pericytes, vascular endothelial cells, smooth muscle cells, and epithelial cells may also be considered.

[0379] In some preceding embodiments, the scaffold material is administered into the wound at the timing immediately after the injury of the wound (for example, the timing when scarring starts in the tissue) or at the initial stage of wound healing. Instead of or in addition to this, it may be administered into the wound at a stage later than those timings and stages.

[0380] In some preceding embodiments, the scaffold material is administered to the wound surface of the wound before scar tissue is formed in the wound and after (or even before) the wound is sutured, whereby the scaffold material is used to perform the anti-scarring treatment in advance.

[0381] In contrast, after the scar tissue in the wound is surgically removed from the living body after the wound has healed naturally in a state where scar tissue has been formed in the wound, and then, after the newly formed wound formed by the excision is sutured in the living body, the scaffold material may be administered to the wound surface of the new wound, whereby the scaffold material may be used to perform the anti-scarring treatment subsequently.

[0382] In some preceding embodiments, the scaffold material is configured as a single-agent liquid preparation in which the biomaterial and the antifibrotic agent are premixed. Instead of this, it may be configured as a single-agent solid preparation.

[0383] In some preceding embodiments, the scaffold material is configured as an injection agent and a patch to be injected into the intra-wound space. Instead of this, it may be configured as a coating agent or an aerosol agent.

[0384] <Supplementary explanation about the above-mentioned multiple scaffold material retention methods>

[0385] Here, when classifying and organizing the plurality of scaffold material placement methods disclosed in this application document without considering the respective material flow characteristics of the biomaterial and the antifibrotic agent as two types of components within the scaffold material, those scaffold material placement methods are first broadly classified into a "placement method within the wound" where the scaffold material is placed within the wound and a "placement method within the abdominal cavity" where the scaffold material is placed within the abdominal cavity.

[0386] That "placement method within the wound" is further classified into a "placement method within the skin suture wound" where it is placed within the skin suture wound and a "placement method within the implant detachment cavity" where the scaffold material is placed in a wound (for example, a wound developed in a spherical shape) formed on the inner surface of the detachment cavity as a closed cavity surrounding the implant.

[0387] To associate those three individual placement methods with FIGS. 3 and 4(a)-(e), the "placement method within the skin suture wound" is associated with FIGS. 3 and 4(a), the "placement method within the abdominal cavity" is associated with FIGS. 4(c)-(e), and the "placement method within the implant detachment cavity" is associated with FIG. 4(b).

[0388] Incidentally, the experimental results shown in FIGS. 8 - 22 are the experimental results obtained when experiments were conducted using mice with the "placement method within the skin suture wound" adopted.

[0389] Regarding that "placement method within the skin suture wound", since both the "placement method within the abdominal cavity" and the "placement method within the implant detachment cavity" share the point that the same attribute scaffold material is used and the point that the scaffold material is placed in the wound at the initial stage of the wound healing process, if experiments are conducted using mice with the latter two placement methods, it is expected that experimental results equivalent to the above experimental results can be obtained, or even if not, at least experimental results indicating that wound healing has occurred in a state of scarring suppression and healing delay suppression can be obtained. Furthermore, as described above, the "placement method within the skin suture wound" is characterized by the "isolated placement of the antifibrotic agent against the skin epithelium".

[0390] In contrast, for the "implant detachment cavity retention method", since there is no skin suture wound as an incision wound, there is no requirement to promote epithelialization in the wound healing process.

[0391] Also, for the "intraperitoneal retention method", as an exemplary embodiment, there is an embodiment in which the abdomen is incised and surgical operations are performed through the incision formed thereby.

[0392] In this exemplary embodiment, among the incision wounds formed in the incision, the portion that appears on the inner surface of the abdominal cavity becomes the healing site (precisely, the site at the aforementioned first retention position) where this retention method is used. Therefore, in this example, if the scaffold material is retained at the healing site, automatically, the scaffold material will be isolated from the skin epithelium.

[0393] Therefore, when the "intraperitoneal retention method" is implemented in this manner, like the "retention method within a skin suture wound", it is characterized by "isolated retention of an anti-fibrotic agent against the skin epithelium".

[0394] <Supplementary Explanation of the "Retention Method within a Skin Suture Wound">

[0395] Hereinafter, the problems to be solved by the "retention method within a skin suture wound" and the technical idea adopted to solve these problems will be described in detail.

[0396] (1) Attributes of the wound to be healed

[0397] In the "retention method within a skin suture wound", the term "wound" is defined as not including "a wound formed by a surgical operation on the eye in a living body" and not including "a defect wound".

[0398] Here, "skin suture wound" inherently does not include "a wound formed by a surgical operation on the eye in a living body".

[0399] By the way, in the "method of implanting in a skin suture wound", the scaffold material composed of an anti-fibrotic agent and a biomaterial acts within the space in the skin suture wound. Since the space in the skin suture wound is exposed on the body surface and communicates with the outside space, the space in the skin suture wound does not correspond to a closed cavity.

[0400] On the other hand, in the "method of implanting in the abdominal cavity" and the "method of implanting in the implant detachment cavity", the scaffold material acts in the abdominal cavity and the detachment cavity as closed cavities, respectively.

[0401] However, these implantation methods have in common that the intact wound is the object to be healed and that the scaffold material is implanted in the intact wound at the initial stage of the wound healing process.

[0402] (2) Summary of the "method of implanting in a skin suture wound"

[0403] As a result of clinical research in which the present inventor participated as a surgeon, When developing a wound scaffold material having both an anti-fibrotic agent and a biomaterial that supports wound healing so that scarring suppression and healing delay suppression are compatible, the wound healing mechanism in a living body (particularly, the mechanism of epithelialization in a wound, or the mechanism by which epithelium in a wound is regenerated) is different depending on whether the wound to be healed is a defective wound in which the skin epithelium is completely discontinuous or an intact wound in which the continuity of the skin epithelium is maintained.

[0404] Specifically, the findings are as follows. Regarding a defective wound, since early epithelialization of the epithelial defect, that is, the early filling of the epithelial defect, is important, it is necessary to apply a biomaterial from the early stage of wound healing. On the other hand, it is necessary to isolate the anti-fibrotic agent from the skin defect. Therefore, when introducing a wound scaffold material having both an anti-fibrotic agent and a biomaterial into the epithelial defect from the early stage of wound healing, a device for primarily isolating the anti-fibrotic agent from the skin defect (primarily blocking the drug effect) (for example, a technique for adjusting the drug elution rate for each drug) is required.

[0405] On the other hand, for a non-defective wound without a tissue defect, wound healing is possible throughout the entire process of wound healing even if scarring is suppressed or without the support of a biomaterial.

[0406] Therefore, the inventor noticed that for a non-defective wound, if a scaffold material is placed in the wound from the early stage of wound healing in a state where an anti-fibrotic agent as a brake for wound healing and a biomaterial as an accelerator for wound healing can act simultaneously, it is possible to achieve both scarring suppression and suppression of healing delay.

[0407] Furthermore, the inventor noticed that if the placement in the wound is performed so that the anti-fibrotic agent is isolated from the skin epithelium, it is possible to more effectively suppress the healing delay caused by the anti-fibrotic agent.

[0408] Based on those findings, the inventor selected a non-defective wound as a treatment target, proposed a wound scaffold material having both an anti-fibrotic agent and a biomaterial that can act without a time difference, and proposed to place the wound scaffold material in the wound at a position isolated from the skin epithelium of the non-defective wound so that the anti-fibrotic agent does not delay epithelialization. The content is disclosed in these application documents.

[0409] (3) The first problem and technical idea in the "method of placing in a skin sutured wound"

[0410] The disclosed matters in these application documents are The first problem is "to suppress scarring at the wound site while suppressing the delay of natural healing of the wound site for a wound in the living body where natural healing should occur". To solve the first problem, the first technical idea is adopted, which is to "simultaneously activate the event of'suppression of scarring by an anti-fibrotic agent → delay of wound healing', which is a metaphor for stepping on the brake in the wound healing process, and the event of 'promotion of proliferation of progenitor cells of myofibroblasts by a biomaterial → promotion of wound healing', which is a metaphor for stepping on the accelerator".

[0411] This first technical idea is embodied by configuring the wound scaffold material as a combined agent (formulation) with an anti-fibrotic agent as the first base or active ingredient and a biomaterial as the second base or active ingredient, thereby enabling the anti-fibrotic agent and the biomaterial to act simultaneously and in parallel.

[0412] (4) The second problem and technical idea in the "method of implanting in a skin suture wound"

[0413] The disclosure of this application document further provides The second problem is "to suppress the inhibition of skin epithelialization by the anti-fibrotic agent and thereby suppress the delay of natural healing, although the anti-fibrotic agent is used as a brake to suppress the differentiation of progenitor cells of myofibroblasts during the wound healing process". To solve the second problem, the second technical idea is adopted, which is to implant the wound scaffold material into the wound so that the anti-fibrotic agent is locally administered at a position isolated from the skin epithelium.

[0414] According to this second technical idea, in the living body, the anti-fibrotic agent is locally administered at a position isolated from the skin epithelium of the wound, thereby preventing the skin epithelium from being exposed to the anti-fibrotic agent.

[0415] As a result, according to the disclosure of this application document, in the wound healing process, although an anti-fibrotic agent is used as a brake to suppress the differentiation of progenitor cells of myofibroblasts, the area where the anti-fibrotic agent is activated as a brake to suppress the inhibition of skin epithelialization and the retardation of natural healing is spatially limited so as not to reach the skin epithelium.

[0416] Furthermore, according to the disclosure of this application document, as is apparent from FIG. 7 and the like, the scaffold material is placed at a position isolated from the epidermis of the skin. Further, when the scaffold material is injected as a liquid agent into the gap of a skin suture wound using an injector or something equivalent thereto (for example, a pipette tip) exemplified in FIG. 23, the tip of the injector is deeply inserted into the gap of the skin suture wound, and as a result, it is apparent that the movement of the liquid agent to the skin epithelium is inhibited.

[0417] As a result, according to the disclosure of this application document, the effect of "suppressing the retardation of natural healing in the presence of an anti-fibrotic agent" is obtained.

[0418] This is also supported by the experimental result comparison table shown in FIG. 12. Specifically, for any control group and any treatment group, skin epithelialization was not observed until the 3rd day after the start of the experiment, but it was confirmed that the wound sites were epithelialized in all groups regardless of the presence or absence of administration of the anti-fibrotic agent, as skin epithelialization was observed on the 7th day.

[0419] This means that in the wound healing process, even in a situation where scarring is suppressed by an anti-fibrotic agent, wound healing is carried out relatively without retardation, that is, without inferiority, compared to a situation where the anti-fibrotic agent is absent.

[0420] That is, according to the disclosure of this application document, in the interior (within the gap) of a wound called a skin suture wound, an anti-fibrotic agent is locally administered at a position isolated from the skin epithelium in the wound, thereby preventing the skin epithelium from being exposed to the anti-fibrotic agent.

[0421] (5) The Third Problem and Technical Concept in the "Retention Method within Skin Suture Wound"

[0422] The disclosure of this application document further sets "achieving both scarring suppression and prevention of delayed wound healing in non-defective wounds" as the third problem, and to solve this third problem, adopts a third technical concept of implanting a scaffold material having both a biomaterial and an anti-fibrotic agent in vivo at the initial stage of the wound healing process.

[0423] Furthermore, in more detail, when the wound is a non-defective wound, if the scaffold material is implanted into the wound at the initial stage of the wound healing process, the differentiation into myofibroblasts is suppressed at the initial stage of the wound healing process. As a result, excessive production of collagen does not occur, and thus excessive scarring is suppressed.

[0424] (6) Regarding the Medical Contribution of the Disclosure of this Application Document, Which Enables the Safe Use of ROCK Inhibitors

[0425] Regarding ROCK inhibitors such as fasudil and lipasudil, several papers have already reported cases where the drug has various effects on keratinocytes that make up the epithelial layer of the skin. In particular, regarding the ROCK inhibitor lipasudil, which is popular as an eye drop, it is well known that blepharitis, a type of skin disease, exists as its side effect. This fact has also been reported in several papers.

[0426] Thus, ROCK inhibitors are drugs that are highly likely to cause skin damage when administered into a wound as anti-fibrotic agents, and therefore, trials on human skin wounds have been avoided.

[0427] In contrast, according to the disclosure of this application document, the antifibrotic agent is not placed alone in the wound, but is placed in the wound in a state of being held or captured in a biomaterial that functions as its carrier, and the biomaterial is placed in a position isolated from the skin epithelium in the wound in a spatially limited manner.

[0428] As a result, it is avoided that the antifibrotic agent moves contrary to intention and reaches the skin epithelium in the wound, so that the skin epithelium, which is an important site for early regeneration in wound healing, is not exposed to the antifibrotic agent.

[0429] Therefore, the disclosure of this application document enables the ROCK inhibitor to be used as an antifibrotic agent in the wound while suppressing its side effects, and contributes medically in this regard.

[0430] <Disclosure of laparotomy method and surgical set for wound healing>

[0431] This application document further discloses, as an exemplary embodiment, a laparotomy method and a surgical set for wound healing including instruments and drugs necessary for performing the laparotomy method and related to wound healing.

[0432] The laparotomy method is performed, for example, partially or completely by a surgeon and / or a robot.

[0433] This laparotomy method is, for example, a laparotomy method of incising the abdominal wall of a patient and performing a treatment on a target organ in the abdominal cavity of the patient.

[0434] This laparotomy method is configured to include an incision step of incising the abdominal wall to thereby form a skin incision wound, a surgical step of performing a surgical operation on the target organ by introducing a surgical instrument from outside the body through the skin incision wound of the abdominal wall into the abdominal cavity, a suturing step of suturing the skin incision wound after completion of the surgical operation to thereby form a skin suture wound, and an introduction step of introducing a wound scaffold material into the formed skin suture wound.

[0435] The wound scaffold material is mainly composed of a bioabsorbable biomaterial and an antifibrotic agent, and is configured such that at least during use of the wound scaffold material, the biomaterial contains the antifibrotic agent.

[0436] The biomaterial is configured to function as an artificial extracellular matrix having a property that precursor cells of the patient's myofibroblasts adhere to the skin suture wound during use.

[0437] In one example, the wound scaffold material is a liquid agent, and the introduction step uses an injector configured to have a main body portion that houses the liquid agent and a nozzle that discharges the housed liquid agent, and includes a step of injecting the wound scaffold material into the skin suture wound with at least the tip of the nozzle inserted into the gap of the skin suture wound.

[0438] An example of the surgical set for wound healing is configured to include the wound scaffold material and the injector.

[0439] In this example, the wound scaffold material and the injector may be configured as one finished product (for example, a product in which the wound scaffold material is pre-filled in the injector), or may be configured as a kit product provided as parts and assembled by an operator on site.

[0440] Furthermore, in some aspects of some of the foregoing embodiments, for the sake of convenience of explanation, as an example of the scaffold material placement method in which the wound scaffold material is placed in the incision formed on the skin as the wound, attention has been paid to a method in which the scaffold material is placed in the incision after the incision is sutured.

[0441] However, instead of that method, it is possible to adopt, as the scaffold material placement method, a method in which the scaffold material is placed in the incision before it is sutured.

[0442] The detailed matters regarding some of the foregoing embodiments or examples have been provided for the purpose of explaining the claims and should not be construed as limiting the scope of the present invention. Although only a few specific examples of the present invention have been described in detail in the above description, those skilled in the art can easily understand that there are many variations in these specific examples without substantially departing from the foregoing novel teachings and the advantages of the present invention. For example, the plurality of features described in connection with one specific example may be combined, whether wholly or in part, with any other specific example of the present invention.

[0443] Therefore, all such variations are intended to be included within the scope of the present invention, and the scope of the present invention is defined in the following claims and all equivalents thereto. Furthermore, many specific examples are assumed not to achieve all of the advantages of some specific examples, particularly the foregoing desirable specific examples, and the absence of a particular advantage does not necessarily mean that the corresponding specific example is not within the scope of the present invention. Since various changes can be made within the foregoing scope without departing from the scope of the present invention, all matters included in the detailed description of the invention should be construed as for explaining the claims and not for limiting.

Claims

1. An artificial wound scaffold to be placed in the abdominal cavity after intraperitoneal laparotomy to suppress adhesions in the abdominal cavity, comprising: The bioabsorbable biomaterial is configured to contain an anti-fibrotic agent; The biomaterial functions as an artificial extracellular matrix having a property to which myofibroblast precursor cells of a living body adhere, and is configured to act as a cell culture scaffold using a hydrogel as a substrate; the antifibrotic agent has a molecular weight of 400 or less and is configured to inhibit differentiation of the precursor cells into the myofibroblasts in the living body, thereby performing antifibrosis on a peritoneal side surgical wound, which is a surgical wound formed in the peritoneum on the abdominal wall side in the abdominal cavity, and an organ side surgical wound, which is a surgical wound formed in a target organ; The wound scaffold is in the form of a sheet, and is placed in the abdominal cavity between the peritoneum and the target organ, and on both sides of the wound scaffold, in surface contact with a local surrounding area of ​​the peritoneum including the peritoneal side surgical wound and a local surrounding area of ​​the target organ including the organ side surgical wound, respectively, thereby making it possible to suppress scarring of each surgical wound and to suppress adhesion between the abdominal wall and the target organ after the intraperitoneal laparotomy.

2. The wound scaffold of claim 1 , wherein the anti-fibrotic agent comprises fasudil or ripasudil.

3. The wound scaffold of claim 1 , wherein the hydrogel comprises gelatin.

4. 2. The wound scaffold of claim 1, wherein the wound scaffold is introduced from outside the body into the abdominal cavity through a skin-side incision made in the abdominal wall and penetrating therethrough during the intraperitoneal laparotomy surgery, and then placed in the abdominal cavity between the peritoneum and the target organ.

5. 10. The wound scaffold of claim 1, wherein the wound scaffold is configured to have low immunogenicity.

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