KR20190092059A - Composition comprising chondrocyte, fibrinogen, collagen or thrombin for arthroscopic cartilage regeneration procedure - Google Patents
Composition comprising chondrocyte, fibrinogen, collagen or thrombin for arthroscopic cartilage regeneration procedure Download PDFInfo
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- KR20190092059A KR20190092059A KR1020180011389A KR20180011389A KR20190092059A KR 20190092059 A KR20190092059 A KR 20190092059A KR 1020180011389 A KR1020180011389 A KR 1020180011389A KR 20180011389 A KR20180011389 A KR 20180011389A KR 20190092059 A KR20190092059 A KR 20190092059A
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- South Korea
- Prior art keywords
- cartilage
- composition
- fibrinogen
- thrombin
- chondrocytes
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Abstract
본 발명은 연골세포, 피브리노겐, 콜라겐 또는 트롬빈을 포함하는 관절경하 수술을 위한 연골 재생용 조성물 및 이의 다양한 적용에 관한 것이다. 본 발명에 따른 관절경하 수술을 위한 연골 재생용 조성물은 연골세포, 피브리노겐, 콜라겐 또는 트롬빈을 특정 비율로 혼합 시, 목적으로 하는 형태로 제작이 가능하고 탄성이 우수하다. 이를 관절경하 수술을 수행하여 연골조직의 손상 부위에 주입 시, 낮은 재생 활성을 갖는 연골의 재생에 유효한 효능을 나타낸다. 또한, 천연물질을 사용하므로 인체에 무해하며, 자연연골과 유사한 조직공학적 연골을 재생하여 손상된 연골조직을 효과적으로 수복할 수 있는 연골 체료제로 유용하게 사용될 수 있다. The present invention relates to compositions for cartilage regeneration for arthroscopic surgery including chondrocytes, fibrinogen, collagen or thrombin and various applications thereof. The composition for cartilage regeneration for arthroscopic surgery according to the present invention can be produced in a desired form and mixed with chondrocytes, fibrinogen, collagen or thrombin in a specific ratio, and excellent in elasticity. When arthroscopic surgery is performed and injected into the damaged area of cartilage tissue, it shows effective efficacy for regeneration of cartilage having low regeneration activity. In addition, the use of natural materials, harmless to the human body, can be used as a cartilage physiological agent that can effectively repair damaged cartilage tissue by regenerating histological cartilage similar to natural cartilage.
Description
본 발명은 연골세포, 피브리노겐, 콜라겐 또는 트롬빈을 포함하는 관절경하 수술을 위한 연골 재생용 조성물 및 이의 다양한 적용에 관한 것이다. The present invention relates to compositions for cartilage regeneration for arthroscopic surgery including chondrocytes, fibrinogen, collagen or thrombin and various applications thereof.
일반적으로 척추동물의 관절을 이루는 연골 조직에는 혈관, 신경 및 임파조직이 없어서 한번 손상되게 되면 정상적으로 생체 내에서 재생이 되지 않는다. 이러한 관절의 연골조직이 손상될 경우 심한 통증과 함께 일상 활동에 제한을 받게 되며, 만성화될 경우 치명적인 퇴행성 관절염을 유발하게 되어 정상적인 생활이나 직업적인 활동을 방해하게 된다. 그러므로 손상된 관절연골은 스스로 회복 및 재생이 매우 제한될 수 밖에 없다. 의학적으로 여러 가지 방법이 도모되지만 아직 관절연골인 초자 연골을 자연과 같은 상태로 회복하기에는 부족한 실정이다.In general, cartilage tissue that forms the joints of vertebrates lack blood vessels, nerves and lymphoid tissues, so once damaged, they do not normally reproduce in vivo. If the cartilage tissue of such a joint is damaged, severe pain and restriction on daily activities, and if chronic, will lead to fatal degenerative arthritis, which interferes with normal living or professional activities. Therefore, damaged articular cartilage can not be very limited in the recovery and regeneration itself. Medically, various methods are promoted, but it is not enough to restore the articular cartilage, which is still articular cartilage, to its natural state.
임상적으로 연골을 재생시키는 수술 방법으로는 ① 줄기세포의 연골세포로의 분화유도를하는 방법, ② 골 연골 이식술(osteochondral transplantation)로 자가 혹은 동종의 연골조직을 연골 결손 부위에 이식하는 방법, ③미세 골절술(microfracture)로 손상된 연골을 잘 긁어내어 제거하고 연골하 골이 노출되면 여기에 일정한 간격으로 구멍을 뚫고 이를 통해서 흘러나온 골수세포가 연골 조직으로 재생되는 것을 도모하는 방법, ④ 연골세포 이식술(chondrocyte transplantation)로 연골 결손부위에 연골세포를 이식함으로써 연골 재생을 유도하는 방법 등이 사용되고 있다.Clinically, surgical methods for regenerating cartilage include: ① inducing differentiation of stem cells into chondrocytes, ② transplanting autologous or homogenous cartilage tissue into cartilage defects by osteochondral transplantation, ③ Microfracture scrapes the damaged cartilage well and removes it. When the subchondral bone is exposed, holes are drilled at regular intervals, and the bone marrow cells flowing through it are regenerated into cartilage tissue. ④ Chondrocyte transplantation The method of inducing cartilage regeneration by transplanting chondrocytes into cartilage defects by (chondrocyte transplantation) has been used.
미세 골절술(microfracture)은 가장 일반적으로 사용되는 방법이며, 그 대표적 방법인 관절경적 시술은 소형카메라가 장착된 관절경(arthroscopy)을 1㎝ 미만의 작은 구멍을 통해 관절강 내에 삽입하여, TV 모니터를 통해 관절 속을 확대 관찰하면서 진단 및 수술을 동시에 수행하는 방법이다. 그러나 미세 골절술(microfracture)은 실제의 관절에 필요한 초자연골(hyaline cartilage)이 아니라 섬유연골(fibro-cartilage)이 주로 생성되기 때문에, 기능적인 측면에서 볼 때는 만족할 만한 효과를 거두지 못하고 있다.Microfracture is the most commonly used method, and arthroscopy, a typical method, involves inserting an arthroscopy with a small camera into the joint cavity through a small hole of less than 1 cm, allowing the TV monitor to It is a method of performing diagnosis and surgery at the same time while expanding the joint inside. However, the microfracture is not a hyaline cartilage required for the actual joints, but fibro-cartilage is mainly produced, and in terms of function, it is not satisfactory.
골 연골 이식술은 환자의 정상부위에서 이미 생성되어 있는 연골과 연골하골 부분을 함께 채취하여, 손상된 연골 부위에 적당한 구멍을 파고 이식하여 초자연골을 생성하는 방법이다. 그러나 상기 방법은 이식된 부위와 원래 조직 사이에 틈이 남는 문제 등이 있어 완전한 치료 방법이라 하기 어려우며, 그나마 자가이식(autolaugous transplantation)이 가능한 환자만을 대상으로 시행할 수 있어 보편적인 방법이 될 수 없다.Bone cartilage transplantation is a method of producing supernatural bone by extracting the cartilage and subchondral bone parts that have already been generated in the normal part of the patient, digging a proper hole in the damaged cartilage area and transplanting them. However, this method is difficult to call a complete treatment because there is a gap between the transplanted site and the original tissue, and it can not be a universal method because it can be performed only in patients capable of autolaugous transplantation. .
최근, 손상된 관절 연골의 치료를 위해 조직 공학에 기초를 둔 새로운 치료법으로서 자기유래 연골세포 이식술이 각광받고 있다. 이는 무릎 관절 연골이 손상된 환자의 연골 부위 중 사용이 많지 않은 연골을 채취한 후 연골 세포를 분리하고, 상기 연골 세포를 배양하여 연골 결손 부위를 치료할 만큼의 연골 세포수를 획득하며, 배양된 연골세포를 환자의 연골 결손 부위에 이식하여 환자의 관절 연골을 복원시키는 방법이다.Recently, self-derived chondrocyte transplantation has been spotlighted as a new treatment based on tissue engineering for the treatment of damaged articular cartilage. This is to extract cartilage that is not used much in the cartilage area of patients with damaged knee joint cartilage, to separate cartilage cells, and to culture the cartilage cells to obtain the number of cartilage cells to treat cartilage defects. It is a method of restoring the joint cartilage of the patient by implanting in the cartilage defect site of the patient.
상기 방법은 이미 생성된 연골조직을 손상부위에 주입하는 골 연골 이식술에 비해, 이식된 연골세포가 손상된 부위 내에서 직접 증식하면서 손상부위를 채우게 되므로, 이식된 부위와 정상 부위가 비교적 잘 융합되며, 초자연골을 재생할 가능성 또한 많다. 그러나 연골세포를 채취할 때, 그리고 체외에서 배양된 연골세포를 다시 관절연골손상 부위에 이식할 때 각각 수술이 필요하므로, 결국 2차례에 걸친 수술에 의해 환자의 고통, 후유증 및 경제적 부담이 크며, 시술 과정 또한 복잡하다. 또한, 채취된 연골세포는 대부분은 이미 성장이 다 이루어진 성인으로부터 얻은 것이므로, 채취된 세포의 증식 및 생장이 왕성하지 않아 세포의 체외 배양시 이식에 필요한 만큼의 세포 수를 얻기까지 상당한 기간이 걸리며, 세포가 분화능력을 잃어 아예 증식하지 않는 경우에는 치료 자체가 이루어질 수 없고, 연골세포를 체외에서 배양하기 때문에 세포의 발현형이 변화되곤 하는 문제점이 있을 수있다.Compared to bone cartilage transplantation, in which the cartilage tissue is already injected into the damaged area, the method can fill the damaged area by directly proliferating the transplanted chondrocytes in the damaged area, so that the transplanted site and the normal site are relatively fused. There are also many possibilities for playing supernatural bones. However, surgery is required when the chondrocytes are harvested and when the chondrocytes cultured in vitro are transplanted to the articular cartilage injuries. Therefore, the patient suffers from pain, sequelae and economic burden by two operations. The procedure is also complicated. In addition, since most of the collected chondrocytes are from adults that have already grown, the proliferation and growth of the collected cells are not so strong that it takes a considerable period of time to obtain as many cells as needed for transplantation in vitro. If the cells lose their differentiation capacity and do not proliferate at all, the treatment itself cannot be achieved, and there may be a problem that the phenotype of the cells is changed because the chondrocytes are cultured in vitro.
상기 방법을 응용하여 자가 유래 골수(bone marrow), 근육, 피부 등의 간엽 조직으로부터 연골세포(chondrocyte)의 전구모세포(precursor cell)인 간엽줄기세포(mesenchymal stem cell; MSC)를 얻고, 체외에서 증식시켜 고분자와 함께 관절연골손상 부위에 주입하는 방법이 보고된 바 있다. 상기와 같이 성숙한 개체에서 얻은 간엽줄기세포를 이용하여 연골손상을 치료하는 방법은 자기유래연골세포 이식술에 비해, 보다 미분화된 세포를 얻어 체외 배양하므로 세포증식력이 다소 높아지는 것으로 나타났다. 그러나 상기 방법 역시 다양한 연골 손상을 충분히 치료하기에는 여전히 미약한 수준의 세포증식력을 나타내고 있다.The method is applied to obtain mesenchymal stem cells (MSCs), which are precursor cells of chondrocytes, from mesenchymal tissues such as bone marrow, muscle, and skin, and proliferate in vitro. Has been reported to inject into the joint cartilage damage site with a polymer. As described above, the method of treating cartilage damage by using mesenchymal stem cells obtained from mature individuals has been shown to increase cell proliferation slightly because of in vitro culture to obtain more undifferentiated cells compared to autologous chondrocyte transplantation. However, the method still shows a weak level of cell proliferation to sufficiently treat various cartilage damage.
이러한 미약한 세포증식력을 개선하기 위하여, 최근에는 제대혈 유래 줄기세포를 관절연골 손상부위에 주입하는 방법이 연구되고 있으나(대한민국공개특허 제10-2003-069115호), 연골 재생 효과 면에서 아직 미흡한 점이 많고, 실제 관절연골 구조를 고려한 지지체에 대한 연구는 아직 없다. In order to improve such weak cell proliferation, a method of injecting umbilical cord blood-derived stem cells into articular cartilage injuries has recently been studied (Korea Patent Publication No. 10-2003-069115). There are many studies on the scaffolding considering the actual articular cartilage structure.
이상으로 볼 때, 연골을 형성하기 위해서는 연골 형성능력이 있는 조직이어야 하고, 기질형성에 필요한 외적 요소를 갖추어야 하며 성장에 필요한 충분한 영양조건을 갖추어야 한다.In view of the above, in order to form cartilage, cartilage forming ability should be a tissue, should have the external elements necessary for the formation of substrate and sufficient nutritional conditions necessary for growth.
따라서, 최근에 손상되었거나 기능을 상실한 환자 자신의 조직이나 장기에서 세포를 일부 채취하여 생체적합성 고분자 지지체를 이용해 체외에서 배양한 다음 체내의 원래 위치에 이식하여 조직이나 장기를 복원, 재생 또는 대체하는 조직공학이 크게 각광을 받고 있다.Thus, tissues that are partially harvested from recently damaged or dysfunctional patients' own tissues or organs, cultured in vitro using biocompatible polymer scaffolds, and transplanted to their original locations in the body to restore, regenerate, or replace tissues or organs. Engineering is in the limelight.
이러한 조직 공학을 이용하여 손상된 연골을 재생하고자 하는 다양한 연구들이 진행되고 있으며, 연골 제조와 관련하여서는 시험관, 배양기 등과 같은 인공적 환경인 차원 담체 구조체에서 제작하거나, 지지체/세포 혼합물을 이용하여 생물체 내(in vivo)에서 제작하는 것이 연구된 바 있다.Various studies have been conducted to regenerate damaged cartilage using this tissue engineering, and in relation to cartilage production, it is manufactured in a dimensional carrier structure, which is an artificial environment such as a test tube, an incubator, or in a living body using a support / cell mixture. In vivo production has been studied.
그러나, 연골 조직을 재생하기 위해서는 앞에서도 서술한 바와 같이 연골 재생층 단독만으로는 한계점이 있다. 연골은 발생학적으로 경골조직과 같은 중배엽에서 기원한 조직으로, 뼈와 함께 내골격을 형성한다. 이처럼 연골과 뼈는 유기적으로 작용하는 조직이지만 종래의 연골과 뼈의 조직공학적 치료는 이들을 각각 치료하였다. 또한 연골 손상이 심한 경우 연골 뿐만 아니라 연골 밑의 골조직 까지 손상을 입는 경우도 있다.However, in order to regenerate cartilage tissue, as described above, the cartilage regeneration layer alone has a limitation. Cartilage is a tissue originated from mesoderm, such as tibial tissue, and forms an endoskeleton with bone. As described above, cartilage and bone are organic tissues, but conventional tissue and cartilage treatment of cartilage and bone treated each of them. In addition, cartilage damage is severely damaged not only cartilage but also bone tissue under the cartilage.
또한, 이런 점을 개선하여 뼈와 연골을 동시에 치료할 수 있는 지지체 개발에 대한 연구가 일부 진행되었으나(대한민국 특허출원 제10-2006-0054236호), 우수한 효과를 가지는 뼈와 연골의 복합 재생용 지지체의 개발이 여전히 요구되고 있는 실정이다.In addition, some studies have been conducted to develop a scaffold that can simultaneously treat bone and cartilage by improving this point (Korean Patent Application No. 10-2006-0054236). Development is still required.
또한 자기 유래 연골세포 이식술과 같이 자신의 조직을 사용할 경우에는 조직을 채취하고 이식을 하는 두 번의 수술이 필요하고, 비용과 시간적 측면에서 많은 문제점을 안고 있다.In addition, when using his own tissues such as autologous chondrocyte transplantation, two surgeries are needed to collect and transplant the tissues, and there are many problems in terms of cost and time.
따라서 효과적이고도 효율적인 관절연골 재생을 위해서는 제품화된 세포를 이용하고, 이를 관절경적 수술 즉 미세 침습적 수술로 치료에 적용해야 환자의 회복이 빠르고 재활이 빨라 사회 경제적 측면에서 큰 이점이 있다. Therefore, for effective and efficient articular cartilage regeneration, it is necessary to use a commercialized cell and apply it to the treatment by arthroscopic surgery, that is, microinvasive surgery.
이에, 본 발명자들은 동종의 연골세포, 피브리노겐, 콜라겐 또는 트롬빈을 특정 비율로 혼합하여 관절경하에 연골조직의 손상 부위에 주입하면 이식물이 관절내에 잘 머물러 효과적으로 손상 부위의 연골 조직을 재생시킬 수 있는 조건을 제공함을 확인함으로써 본 발명을 완성하였다. Accordingly, the present inventors mixed the same kind of cartilage cells, fibrinogen, collagen or thrombin at a specific ratio and injecting the cartilage tissue injured area under arthroscopy, whereby the implant stays well in the joint to effectively regenerate cartilage tissue at the damaged area. The present invention has been completed by confirming that the conditions are provided.
본 발명의 목적은 피브리노겐 및 콜라겐을 포함하는 제1조성물; 및 연골세포 및 트롬빈을 포함하는 제2조성물을 포함하는, 관절경하 수술을 위한 연골 재생용 조성물을 제공하는 것이다. An object of the present invention is a first composition comprising fibrinogen and collagen; And a second composition comprising chondrocytes and thrombin, to provide a composition for cartilage regeneration for arthroscopic surgery.
본 발명의 또 다른 목적은 (a) 피브리노겐 및 콜라겐을 포함하는 제1조성물을 제조하고, 연골세포 및 트롬빈을 포함하는 제2조성물을 제조하는 단계; 및 (b) 상기 (a)단계의 제1조성물 및 제2조성물을 혼합하고 골 또는 연골 손상 조직부위에 주입하는 단계를 포함하는 관절경하 수술을 위한 연골 재생 방법을 제공하는 것이다. Still another object of the present invention is to prepare a first composition comprising fibrinogen and collagen, and to prepare a second composition comprising chondrocytes and thrombin; And (b) mixing the first composition and the second composition of step (a) and injecting the bone or cartilage damaged tissue into the cartilage regeneration method for arthroscopic surgery.
상기 목적을 달성하기 위하여, 본 발명은 피브리노겐 및 콜라겐을 포함하는 제1조성물; 및 연골세포 및 트롬빈을 포함하는 제2조성물을 포함하는 관절경하 수술을 위한 연골 재생용 조성물을 제공한다. In order to achieve the above object, the present invention comprises a first composition comprising fibrinogen and collagen; And it provides a composition for cartilage regeneration for arthroscopic surgery comprising a second composition comprising chondrocytes and thrombin.
또한 본 발명은 (a) 피브리노겐 및 콜라겐을 포함하는 제1조성물을 제조하고, 연골세포 및 트롬빈을 포함하는 제2조성물을 제조하는 단계; 및 (b) 상기 (a)단계의 제1조성물 및 제2조성물을 혼합하고 골 또는 연골 손상 조직부위에 주입하는 단계를 포함하는 관절경하 수술을 위한 연골 재생 방법을 제공한다.In addition, the present invention comprises the steps of (a) preparing a first composition comprising fibrinogen and collagen, and preparing a second composition comprising chondrocytes and thrombin; And (b) mixing the first composition and the second composition of step (a) and injecting the bone or cartilage damaged tissue into the cartilage regeneration method for arthroscopic surgery.
본 발명에 따른 관절경하 수술을 위한 연골 재생용 조성물은 연골세포, 피브리노겐, 콜라겐 또는 트롬빈을 특정 비율로 혼합 시, 목적으로 하는 형태로 제작이 가능하고 탄성이 우수하다. 이를 관절경하 수술을 수행하여 연골조직의 손상 부위에 주입 시, 낮은 재생 활성을 갖는 연골의 재생에 유효한 효능을 나타낸다. 또한, 천연물질을 사용하므로 인체에 무해하며, 자연연골과 유사한 조직공학적 연골을 재생하여 손상된 연골조직을 효과적으로 수복할 수 있는 연골 체료제로 유용하게 사용될 수 있다. The composition for cartilage regeneration for arthroscopic surgery according to the present invention can be produced in a desired form and mixed with chondrocytes, fibrinogen, collagen or thrombin in a specific ratio, and excellent in elasticity. When arthroscopic surgery is performed and injected into the damaged area of cartilage tissue, it shows effective efficacy for regeneration of cartilage having low regeneration activity. In addition, the use of natural materials, harmless to the human body, can be used as a cartilage physiological agent that can effectively repair damaged cartilage tissue by regenerating histological cartilage similar to natural cartilage.
도 1은 본 발명의 연골 재생용 조성물을 준비하는 과정을 도식화하여 나타낸 것이다.
도 2는 실험예 1의 각 구성에 따른 조성물의 비드 형태를 확인한 도이다.
도 3은 실험예 2의 각 구성에 따른 조성물의 비드 형태를 확인한 도이다.
도 4는 실험예 3의 각 구성에 따른 조성물의 비드 형태를 확인한 도이다.1 is a schematic diagram illustrating a process of preparing a composition for cartilage regeneration of the present invention.
2 is a view confirming the bead form of the composition according to each configuration of Experimental Example 1.
3 is a view confirming the bead form of the composition according to each configuration of Experimental Example 2.
4 is a view confirming the bead form of the composition according to each configuration of Experimental Example 3.
본 발명은 피브리노겐 및 콜라겐을 포함하는 제1조성물; 및 연골세포 및 트롬빈을 포함하는 제2조성물을 포함하는, 관절경하 수술을 위한 연골 재생용 조성물을 제공한다. The present invention comprises a first composition comprising fibrinogen and collagen; And it provides a composition for cartilage regeneration for arthroscopic surgery, including a second composition comprising chondrocytes and thrombin.
본 발명에서 용어,연골은 연골세포와 그것을 둘러싸는 다량의 기질로 된 뼈로 이것에 대해 보통 말하는 뼈는 경골이다. 기질의 구성성분에 따라 초자연골, 탄성연골, 섬유연골로 나눈다. 연골의 작용에는 관절의 골단을 덮는 관절연골에서 볼 수 있는 것처럼 골단의 마찰을 방지하는 외에 기관, 귓바퀴와 같이 탄력을 유지하거나, 늑연골, 치골결합 연골과 같이 압력에 대한 저항력을 주는 것 등을 들 수 있다.In the present invention, the term "cartilage" is a bone made of chondrocytes and a large amount of matrix surrounding the bone, which is commonly referred to as tibia. Depending on the composition of the substrate, it is divided into supernatural bone, elastic cartilage, fibrocartilage. The effects of cartilage include the prevention of friction of the tip, as seen in the joint cartilage that covers the end of the joint, as well as maintaining elasticity, such as the trachea and the auricle, or resistance to pressure, such as the costal cartilage and pubic cartilage. Can be.
초자연골에서는 기질이 반투명하고, 언뜻 보아 균일하며 무구조로 보이나 수분이 많고(60 ~ 80%), 황산콘드로이틴을 가지는 복합단백질(무코이드)을 포함하며, 늑연골, 비연골, 후두연골, 관절연골, 기관연골 등이 속한다. 탄성연골은 기질 중에 탄성섬유가 들어 있어 쉽게 만곡되며, 귓바퀴 연골, 외이도, 후두개 등이 속한다. 섬유연골에는 많은 교원질섬유가 들어 있어, 추간원판연골, 치골결합연골, 관절원판(악관절, 흉쇄관절에 있음) 등이 속한다. In supernatural bones, the substrate is translucent, at first glance uniform and non-structured, but rich in moisture (60 to 80%), and contains complex protein (cooid) with chondroitin sulfate, including the costal, non-cartilage, laryngeal cartilage, articular cartilage, Organ cartilage, etc. belong. Elastic cartilage is easily curved because it contains elastic fibers in the substrate, the ear cartilage, the ear canal, the larynx, etc. belong. Fibrous cartilage contains a lot of collagen fibers, intervertebral disc cartilage, interosseous cartilages, articular discs (in the jaw joint, sternal joint), etc. belong.
이러한 연골조직이 손상될 경우 스스로 회복 및 재생이 매우 제한되며, 의학적으로 여러 가지 방법이 시도되고 있지만 아직 관절연골인 초자연골을 자연과 같은 상태로 회복하기에는 부족한 실정이다.When such cartilage tissue is damaged, recovery and regeneration are very limited on their own, and various methods have been tried medically, but it is not enough to recover the superficial bone, which is articular cartilage, to a natural state.
상기 조성물은 생체 적합성 물질로서 피브리노겐, 콜라겐 또는 트롬빈을 이용할 수 있다.The composition may use fibrinogen, collagen or thrombin as biocompatible materials.
본 발명에 있어서, 용어 생체적합성은 생체조직 또는 혈액과 접촉하여 조직을 괴사시키거나 혈액을 응고시키지 않는 조직적합성 및 혈액적합성을 의미하며, 생체적합성 고분자란 이러한 생체적합성을 갖추고 있는 고분자를 의미한다. In the present invention, the term biocompatibility refers to histocompatibility and blood compatibility that does not cause necrosis or coagulation of tissue in contact with living tissue or blood, and biocompatible polymer refers to a polymer having such biocompatibility.
본 발명에서 가교활성 촉매제로서 트롬빈을 사용할 수 있으며, 피브리노겐은 응고인자 역할로서 사용할 수 있다. Thrombin may be used as the crosslinking catalyst in the present invention, and fibrinogen may be used as a coagulation factor.
상기 트롬빈은 혈액 응고에 관계되는 단백질 분해효소의 일종으로, 혈장 속에서는 프로트롬빈으로 존재하며, 출혈 시에 혈소판이 파괴되어 트롬보플라스틴이 혈장 중에 나오면 혈액의 칼슘이온의 존재 하에 활성화되어 트롬빈이 된다. 또한, 혈액 응고의 본질인 혈액 속의 가용성 피브리노겐을 가수분해하여 불용성인 피브린으로 변화시키는 반응을 촉매한다. 피브리노겐에 대한 기질 특이성이 매우 높고 피브리노겐의 4개의 펩티드 결합을 자르는데, 그 곳은 아르지닌과 글리신 잔기 사이이다. 최적 pH는 중성 또는 약알칼리성 부근이다. 주성분은 단백질로 최소분자량은 8,000이며 중합하기 쉬운 성질을 갖는다. The thrombin is a kind of proteolytic enzyme related to blood coagulation, and exists in the plasma as prothrombin. When platelets are destroyed during bleeding and thromboplastin comes out of plasma, thrombin is activated in the presence of calcium ions in the blood to become thrombin. It also catalyzes the reaction of hydrolyzing soluble fibrinogen in the blood, which is the essence of blood coagulation, to change to insoluble fibrin. The substrate specificity for fibrinogen is very high and the four peptide bonds of fibrinogen are cut, between the arginine and glycine residues. The optimum pH is near neutral or slightly alkaline. Its main component is protein, which has a minimum molecular weight of 8,000 and is easy to polymerize.
본 발명에서 용어,관절경은 관절강내의 변화를 직접 관찰하거나 사진으로 촬영하는 장치로서, 약간 굵은 천자침에 전구와 반사경을 장치하여 관절강 내에 꽂아넣고 전기조명에 의하여 반사경을 통해 관찰하는 것을 의미한다. 본 발명의 목적 상, 관절경을 수행 시, 골조직의 손상 부위를 관찰하면서 본 발명의 조성물 손상 부위에 주입하면 정확하게 주입 가능하고, 이식물이 관절내에 잘 머물러 효과적으로 손상 부위의 연골 조직을 재생시킬 수 있다. In the present invention, the term "arthroscopy" is a device for directly observing or photographing a change in the joint cavity, and means placing a light bulb and a reflector in a slightly thick puncture needle and inserting it into the joint cavity and observing through the reflector by electric light. For the purposes of the present invention, when performing arthroscopy, the injection of the composition of the present invention while observing the damaged area of the bone tissue can be accurately injected, and the implant can stay in the joint well to effectively regenerate the cartilage tissue of the damaged area. have.
본 발명에서는 피브리노겐 및 콜라겐은 각각 7:3 ~ 9:1의 혼합비율로 혼합할 수 있으며, 가장 바람직하게는 8:2의 혼합비율일 수 있다. In the present invention, fibrinogen and collagen may be mixed in a mixing ratio of 7: 3 to 9: 1, respectively, and most preferably, a mixing ratio of 8: 2.
또한, 연골세포 및 트롬빈은 각각 7:3 ~ 9:1의 혼합비율로 혼합할 수 있으며, 가장 바람직하게는 8:2의 혼합비율일 수 있다.In addition, chondrocytes and thrombin may be mixed at a mixing ratio of 7: 3 to 9: 1, respectively, and most preferably at a mixing ratio of 8: 2.
나아가 본 발명에 따른 관절경하 수술을 위한 연골 재생용 조성물은 항균성 부여를 위해 항생제를 추가로 포함할 수도 있다. 항생제는 당업계에 세균의 생육과 활성을 저지 또는 억제할 수 있다고 알려진 것이라면 어느 것이나 사용할 수 있으며, 대표적인 예로는 암피실린(ampicillin), 젠타마이신(gentamicin), 메틸파라벤(methyl paraben), 에틸파라벤(ethyl paraben), 페니실린(penicillin), 세팔로스포린(cephalosporin), 모노박탐(monobactam), 카바페넴(carbapenem), 아미노글리코사이드(aminoglycoside), 마크롤라이드(macrolide), 테트라사이클린(tetracycline), 클로르암페니콜(chloramphnicol), 퀴놀론(quinolone), 반코마이신(vancomycin), 테이코플라닌(teicoplanin), 린코사미드(lincosamide), 메트로니다졸(metronidazole), 설폰아미드(sulfonamide), 트리메소프림(trimethoprim) 및 이들의 염이 포함되고, 이들은 단독으로 또는 2종 이상의 혼합물 형태로 사용될 수 있다. 이때 항생제는 각 항생제가 표적으로 하는 세균의 생육 및 활성을 저지하거나 억제하는데 최적으로 알려진 농도로 사용할 수 있다.Furthermore, the composition for cartilage regeneration for arthroscopic surgery according to the present invention may further include an antibiotic for imparting antimicrobial activity. Antibiotics can be used as long as they are known in the art to inhibit or inhibit the growth and activity of bacteria, and representative examples are ampicillin, gentamicin, methyl paraben, ethyl paraben, and ethyl paraben. paraben, penicillin, cephalosporin, monoobactam, carbapenem, aminoglycoside, macrolide, tetracycline, chloramphenyline Chloramphnicol, quinolone, vancomycin, teicoplanin, teicoplanin, lincosamide, metronidazole, sulfonamide, trimethoprim and their Salts are included and they can be used alone or in the form of mixtures of two or more. Antibiotics may be used at concentrations best known to inhibit or inhibit the growth and activity of the bacteria targeted by each antibiotic.
또한 본 발명은 (a) 피브리노겐 및 콜라겐을 포함하는 제1조성물을 제조하고, 연골세포 및 트롬빈을 포함하는 제2조성물을 제조하는 단계; 및 (b) 상기 (a)단계의 제1조성물 및 제2조성물을 혼합하고 골 또는 연골 손상 조직부위에 주입하는 단계를 포함하는 관절경하 수술을 위한 연골 재생 방법을 제공한다. In addition, the present invention comprises the steps of (a) preparing a first composition comprising fibrinogen and collagen, and preparing a second composition comprising chondrocytes and thrombin; And (b) mixing the first composition and the second composition of step (a) and injecting the bone or cartilage damaged tissue into the cartilage regeneration method for arthroscopic surgery.
본 발명에서는 피브리노겐 및 콜라겐은 각각 7:3 ~ 9:1의 혼합비율로 혼합할 수 있으며, 가장 바람직하게는 8:2의 혼합비율일 수 있다. In the present invention, fibrinogen and collagen may be mixed in a mixing ratio of 7: 3 to 9: 1, respectively, and most preferably, a mixing ratio of 8: 2.
또한, 연골세포 및 트롬빈은 각각 7:3 ~ 9:1의 혼합비율로 혼합할 수 있으며, 가장 바람직하게는 8:2의 혼합비율일 수 있다.In addition, chondrocytes and thrombin may be mixed at a mixing ratio of 7: 3 to 9: 1, respectively, and most preferably at a mixing ratio of 8: 2.
상기 (b) 단계는 0.5~20분간 겔화시키는 단계를 더 포함할 수 있고, 바람직하게는 0.5~10분간 겔화시키는 것이나, 이에 제한되지 않는다. The step (b) may further comprise a step of gelling for 0.5 to 20 minutes, preferably to be gelated for 0.5 to 10 minutes, but is not limited thereto.
또한, 본 발명은 피브리노겐 및 콜라겐을 포함하는 제1조성물; 및 연골세포 및 트롬빈을 포함하는 제2조성물을 포함하는 연골 손상 치료용 조성물을 제공한다. In addition, the present invention comprises a first composition comprising fibrinogen and collagen; And it provides a composition for treating cartilage damage comprising a second composition comprising chondrocytes and thrombin.
본 발명에 따른 연골 손상 치료용 조성물은 두개안면, 귓바퀴, 코, 관절 등의 외상, 선천기형, 이물 제거부, 노화에 따른 변성 등에 의해 발생된 연골 결손부의 수복에 유용하게 사용될 수 있다.The composition for treating cartilage damage according to the present invention can be usefully used for repairing cartilage defects caused by trauma of the cranial face, auricle, nose, joints, congenital malformations, foreign body removal, degeneration due to aging, and the like.
본 발명에 따르면 결합조직의 손상 부위, 특히 낮은 재생 활성을 갖는 연골을 효과적으로 재생시킬 수 있으며, 천연물질을 사용하므로 인체에 무해하며, 자연 연골과 유사한 조직공학적 연골을 재생하여 손상된 연골조직을 효과적으로 수복할 수 있는 연골 치료제로 유용하게 사용될 수 있다.According to the present invention, it is possible to effectively regenerate damaged areas of the connective tissue, in particular cartilage having a low regeneration activity, harmless to the human body by using natural materials, and effectively repair damaged cartilage tissue by regenerating histological cartilage similar to natural cartilage. It can be usefully used as a therapeutic agent for cartilage.
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
<실시예 1> 관절 내시경 시술에 적용 가능한 생체 재료와 연골세포의 혼합방법Example 1 Mixing Method of Biomaterials and Chondrocytes Applicable to Arthroscopy
본 발명자들은 관절 내시경 시술 시에 수술부위에 잘 고정, 적용이 되는 조성비를 도출하기 위하여 하기 표 1과 같이 구성을 달리한 재료들을 혼합하여 관절 내시경 시술에 적용하였다. The present inventors applied to joint endoscopy by mixing materials having different configurations as shown in Table 1 to derive a composition ratio that is well fixed and applied to the surgical site during arthroscopy.
구체적으로, 그린 플라스트큐(Greenplast Q)에 트롬빈과 피브리노겐을 각각 주입한 후 하기 표 1에 기재되어 있는 제1조성물 및 제2조성물의 혼합 비율에 알맞은 트롬빈, TGF-β1 유전자 도입 연골 세포(Invossa-K Inj, 코오롱 생명과학) 및 콜라겐을 각각 준비하였다. 3way를 이용하여 혼합하였으며, 실린지에 장착 후 Y자 관과 니들(needle)을 실린지의 연결부위에 고정하여 관절경 시술에 사용할 수 있도록 세팅하였으며, 도 1 및 하기 표 1과 같이 혼합비율을 달리한 조성물을 시험관에 떨어뜨려 비드의 농도 및 굳기를 확인하였다. Specifically, thrombin and TGF-β1 transgenic chondrocytes suitable for the mixing ratio of the first composition and the second composition described in Table 1 after injecting thrombin and fibrinogen into Greenplast Q respectively (Invossa) -K Inj, Kolon Life Sciences) and collagen, respectively. After mixing using 3way, the Y-shaped tube and the needle (needle) was fixed to the connection part of the syringe after mounting in the syringe was set to be used for arthroscopy, and the mixing ratio was changed as shown in Figure 1 and Table 1 below. The composition was dropped in a test tube to check the concentration and firmness of the beads.
실험예 1에 따른 관절 내시경 시술에 적용 가능한 생체 재료와 연골세포의 최적 조성비 확인Confirmation of Optimal Composition Ratio of Biomaterials and Chondrocytes Applicable to Endoscopic Procedures According to Experimental Example 1
관절경 수술 시 조작과 유지가 용이한 연골재생용 조성물의 최적 혼합비를 도출하기 위하여, 상기 표 1의 각 구성에 따라, 제1조성물로서 피브리노겐을, 제2조성물로서 연골 세포 및 트롬빈을 혼합하였다. 그 후, 상기 실시예 1의 방법으로 제1조성물 및 제2조성물을 혼합하여 비드의 형태 및 굳기를 확인하였다. 그 결과를 도 2에 나타내었다.In order to derive the optimum mixing ratio of the composition for cartilage regeneration that is easy to operate and maintain during arthroscopy, according to each configuration of Table 1, fibrinogen was mixed as a first composition and chondrocytes and thrombin as a second composition. Thereafter, the first composition and the second composition were mixed by the method of Example 1 to check the form and firmness of the beads. The results are shown in FIG.
그 결과, 구성 1의 비율로 혼합된 조성물의 비드는 형태를 유지하지 않고 그 모양이 무너지고 흘러내렸다. 또한, 구성 4, 5의 비드는 빠른 시간에 형태를 유지하였으나 압력을 가했을 때 모양이 변형되어 연골 재생용 조성물로서 사용하기 적합하지 않음을 확인하였다. 구성 2, 3의 비드는 형태를 구성함에 있어서 흘러내리거나 빠르게 굳지 않는 형태임을 확인하였다.As a result, the beads of the composition mixed at the ratio of the constitution 1 did not retain their shape and the shape collapsed and flowed down. In addition, it was confirmed that the bead of the configuration 4, 5 was maintained in a quick time, but the shape is deformed when the pressure is applied, it is not suitable for use as a composition for cartilage regeneration. Beads of components 2 and 3 confirmed that the form does not flow down or harden quickly in constructing the form.
따라서, 실험예 1을 통하여, 구성 2, 3의 조성물이 가장 용이함을 확인하였으며, 본 발명의 연골 재생용 조성물은 연골 세포가 0.7~0.8㎖ 가 포함되는 비율로 구성을 해야 비드의 형태를 유지함을 확인하였다. Therefore, through Experimental Example 1, it was confirmed that the composition of the composition 2, 3 is the easiest, the composition for cartilage regeneration of the present invention to maintain the form of the bead should be composed of cartilage cells in a ratio containing 0.7 ~ 0.8ml. Confirmed.
실험예 2에 따른 관절 내시경 시술에 적용 가능한 생체 재료와 연골세포의 최적 조성비 확인Confirmation of Optimum Composition Ratio of Biomaterials and Chondrocytes Applicable to Endoscopic Procedures According to Experimental Example 2
관절경 수술 시 조작과 유지가 용이한 연골재생용 조성물의 최적 혼합비를 도출하기 위하여, 상기 표 1의 각 구성에 따라, 제1조성물로서 피브리노겐 및 연골세포를 혼합하고, 제2조성물로서 연골 세포 및 트롬빈을 각 비율로 혼합하였다. 그 후, 상기 실시예 1의 방법으로 제1조성물 및 제2조성물을 30회 이상 믹싱하였으며, 이 후 비드의 형태 및 굳기를 확인하였다. 그 결과를 도 3에 나타내었다.In order to derive the optimum mixing ratio of the composition for cartilage regeneration that is easy to operate and maintain during arthroscopy, according to the configuration of Table 1, fibrinogen and chondrocytes are mixed as the first composition, and cartilage cells and the second composition. Thrombin was mixed in each ratio. Thereafter, the first composition and the second composition were mixed 30 times or more by the method of Example 1, after which the shape and firmness of the beads were confirmed. The results are shown in FIG.
그 결과, 구성 3의 비율로 혼합된 조성물은 비드의 형태를 제대로 유지하지 못하고 퍼지는 것을 확인하였다. 구성 1의 비율로 혼합된 비드는 제1조성물과 제2조성물이 혼합되면서 비교적 비드의 형태유지에 있어서 좋았으나 전반적으로 굳기가 늦어지는 양상을 보였다.As a result, it was confirmed that the composition mixed in the ratio of the constitution 3 did not properly maintain the form of the beads and spread. Beads mixed in the ratio of Composition 1 were relatively good in maintaining the shape of the beads as the first composition and the second composition were mixed, but the overall hardness was slowed down.
구성 2, 3의 비율로 혼합된 조성물에서도 비드의 형태는 유지되었지만 빠르게 굳지 않음을 확인하였다. 실험 2는 가능한 한 많은 양의 세포를 이식물에 삽입하고자 실험한 것으로 피브리노겐에 세포를 추가하는 것은 관절경하 이식을 위해서는 적합하지 못함을 확인하였다. Even in the composition mixed in the ratio of components 2 and 3, it was confirmed that the form of beads was maintained but did not harden rapidly. Experiment 2 experimented to insert as much of the cell as possible into the implant and confirmed that adding cells to fibrinogen is not suitable for arthroscopic transplantation.
실험예 3에 따른 관절 내시경 시술에 적용 가능한 생체 재료와 연골세포의 최적 조성비 확인Confirmation of Optimal Composition Ratio of Biomaterials and Chondrocytes Applicable to Endoscopic Procedures According to Experimental Example 3
관절경 수술 시 조작과 유지가 용이한 연골재생용 조성물의 최적 혼합비를 도출하기 위하여, 상기 표 1의 각 구성에 따라, 제1조성물로서 피브리노겐 및 콜라겐을 혼합하였다. 또한, 제2조성물로서 연골 세포 및 트롬빈을 위의 실험을 통해 얻어진 최적의 비율로 혼합하였다. 그 후, 상기 실시예 1의 방법으로 제1조성물 및 제2조성물을 30회 이상 믹싱하였으며, 비드의 형태 및 굳기를 확인하였다. 그 결과를 도 4에 나타내었다.In order to derive the optimum mixing ratio of the composition for cartilage regeneration that is easy to operate and maintain during arthroscopy, according to each configuration of Table 1, fibrinogen and collagen were mixed as the first composition. In addition, cartilage cells and thrombin as a second composition was mixed in the optimum ratio obtained through the above experiment. Thereafter, the first composition and the second composition were mixed at least 30 times by the method of Example 1, and the shape and firmness of the beads were confirmed. The results are shown in FIG.
그 결과, 구성 1, 2의 비율로 혼합된 조성물은 비드의 형태가 제대로 형성되면서 압력을 가하여도 퍼지지 않고 흘러내리지 않음을 확인하였다. 이중 구성 1이 구성 2보다 조금 더 비즈의 굳기가 단단하고 형태가 변형되지 않았다.As a result, it was confirmed that the composition mixed in the ratio of the constitutions 1 and 2 did not flow without spreading even under pressure while the beads were properly formed. The dual configuration 1 was slightly harder in the beads than configuration 2 and did not deform in shape.
또한 구성 2의 비율로 혼합된 조성물도 비드의 형태가 제대로 형성되었으나, 압력을 가하였을 때 형태가 약간 변형되고 재료가 새어 나옴을 확인하였다. In addition, the composition mixed in the ratio of the composition 2, but the form of the beads were properly formed, it was confirmed that when the pressure is slightly deformed and the material leaks.
따라서, 구성 1의 조성물인 콜라겐 0.2㎖ + 피브리노겐 0.8㎖ / 연골세포 0.8㎖ + 트롬빈 0.2㎖ 혼합하였을 때 가장 최적인 것으로 확인하였다. Therefore, it was confirmed that it is most optimal when mixing 0.2 ml of collagen + 0.8 ml of fibrinogen / 0.8 ml of chondrocytes + 0.2 ml of thrombin, which is the composition of Composition 1.
Claims (9)
연골세포 및 트롬빈을 포함하는 제2조성물을 포함하는 관절경하 수술을 위한연골 재생용 조성물.A first composition comprising fibrinogen and collagen; And
Cartilage regeneration composition for arthroscopic surgery comprising a second composition comprising chondrocytes and thrombin.
상기 조성물은 생체 내에서 혼합되는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생용 조성물.The method of claim 1,
The composition is a composition for cartilage regeneration for arthroscopic surgery, characterized in that mixed in vivo.
상기 조성물은 관절경 수술 또는 시술에 사용하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생용 조성물.The method of claim 1,
The composition is a composition for cartilage regeneration for arthroscopic surgery, characterized in that used for arthroscopy or surgery.
상기 피브리노겐 및 콜라겐은 7:3 ~ 9:1의 혼합비율로 혼합하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생용 조성물.The method of claim 1,
The fibrinogen and collagen composition for cartilage regeneration for arthroscopic surgery, characterized in that the mixing ratio of 7: 3 to 9: 1.
상기 연골세포 및 트롬빈은 7:3 ~ 9:1의 혼합비율로 혼합하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생용 조성물.The method of claim 1,
The cartilage cells and thrombin is a composition for cartilage regeneration for arthroscopic surgery, characterized in that the mixing ratio of 7: 3 to 9: 1.
(b) 상기 (a)단계의 제1조성물 및 제2조성물을 혼합하고 골 또는 연골 손상 조직부위에 주입하는 단계를 포함하는 관절경하 수술을 위한 연골 재생 방법.(a) preparing a first composition comprising fibrinogen and collagen and preparing a second composition comprising chondrocytes and thrombin; And
(B) cartilage regeneration method for arthroscopic surgery comprising the step of mixing the first composition and the second composition of step (a) and injected into the bone or cartilage damaged tissue.
상기 피브리노겐 및 콜라겐은 7:3 ~ 9:1의 혼합비율로 혼합하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생 방법.The method of claim 6,
The fibrinogen and collagen is cartilage regeneration method for arthroscopic surgery, characterized in that the mixing ratio of 7: 3 to 9: 1.
상기 연골세포 및 트롬빈은 7:3 ~ 9:1의 혼합비율로 혼합하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생 방법.The method of claim 6,
The chondrocyte and thrombin are cartilage regeneration method for arthroscopic surgery, characterized in that the mixing ratio of 7: 3 to 9: 1.
상기 (b) 단계는 0.5~20분간 겔화시키는 단계를 더 포함하는 것을 특징으로 하는 관절경하 수술을 위한 연골 재생 방법.The method of claim 6,
The step (b) is cartilage regeneration method for arthroscopic surgery, characterized in that it further comprises the step of gelling for 0.5 to 20 minutes.
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| KR1020180011389A KR20190092059A (en) | 2018-01-30 | 2018-01-30 | Composition comprising chondrocyte, fibrinogen, collagen or thrombin for arthroscopic cartilage regeneration procedure |
| KR1020220059680A KR102520363B1 (en) | 2018-01-30 | 2022-05-16 | Composition comprising chondrocyte, fibrinogen, collagen or thrombin for arthroscopic cartilage regeneration procedure |
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| KR102273121B1 (en) * | 2020-06-26 | 2021-07-06 | 주식회사 덴하우스 | Injectable composition for bone regeneration |
| WO2022092515A1 (en) * | 2020-10-29 | 2022-05-05 | 주식회사 덴하우스 | Freeze-dried collagen-sponge-type composition for bone regeneration |
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| KR100774089B1 (en) * | 2005-07-20 | 2007-11-06 | 세원셀론텍(주) | Implantation method of injectable chondrocyte therapy |
| US20080181879A1 (en) * | 2007-01-18 | 2008-07-31 | Baxter International Inc. | Fibrin gel for controlled release of tgf-beta and uses thereof |
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| WO2021261954A1 (en) * | 2020-06-26 | 2021-12-30 | 덴하우스 주식회사 | Injectable composition for bone regeneration |
| WO2022092515A1 (en) * | 2020-10-29 | 2022-05-05 | 주식회사 덴하우스 | Freeze-dried collagen-sponge-type composition for bone regeneration |
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