KR20070073008A - Injectable hydrogels based on hyaluonic acid for tissue regeneration - Google Patents

Injectable hydrogels based on hyaluonic acid for tissue regeneration Download PDF

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KR20070073008A
KR20070073008A KR1020060000463A KR20060000463A KR20070073008A KR 20070073008 A KR20070073008 A KR 20070073008A KR 1020060000463 A KR1020060000463 A KR 1020060000463A KR 20060000463 A KR20060000463 A KR 20060000463A KR 20070073008 A KR20070073008 A KR 20070073008A
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박용두
이규백
김정주
태기융
황순정
노인섭
경 선
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Abstract

Provided are an acrylated hyaluronic acid derivative or its salt, its preparation method, a crosslinked hydrogel using the derivative or salt which can be injected in vivo and regenerates tissue with minimum damage, and a composition for regenerating tissue or preventing re-adsorption containing the hydrogel. The acrylated hyaluronic acid derivative is represented by the formula(1), wherein R is -NH-CO-(CH2)n-CO-NH-; and n is 4-8. The acrylated hyaluronic acid derivative is prepared by reacting hyaluronic acid and a diamine represented by H2N-R-NH2 in the presence of a polymerizing agent; and reacting the obtained one with an acrylating agent. Preferably the acrylating agent is N-acryloxysuccinimide. The hydrogel is prepared by crosslinking the acrylated hyaluronic acid derivative of the formula(1) or its salt with a crosslinking agent having a thiol group.

Description

조직재생을 위한 히알루론산-기초된 주사형 하이드로겔{Injectable hydrogels based on hyaluonic acid for tissue regeneration} Injectable hydrogels based on hyaluonic acid for tissue regeneration

도 1은 합성된 하이드로겔의 사진이다. 1 is a photograph of the synthesized hydrogel.

도 2는 FR-IR (Fourier transformed infrared) 분광학을 이용하여 아크릴화된 히알루론산을 확인한 것이다. Figure 2 confirms the acrylated hyaluronic acid using Fourier transformed infrared (FR-IR) spectroscopy.

도 3은 유량계(rheometer)를 이용하여 하이드로겔 생성 속도를 측정한 그래프이다. Figure 3 is a graph measuring the hydrogel production rate using a rheometer (rheometer).

도 4는 히알루로니다제에 의한 히알루론산-기초된 하이드로겔의 분해 양상을 나타내는 그래프이다. 4 is a graph showing the degradation of hyaluronic acid-based hydrogels with hyaluronidase.

도 5는 본 발명에 따라 제조된 하이드로겔을 사용하여 경조직 재생을 관측한 조직화학염색사진이다. 5 is a histochemical staining photograph of hard tissue regeneration using a hydrogel prepared according to the present invention.

본 발명은 아크릴화된 히알루론산 유도체 또는 이의 염, 이를 사용하여 제조 된 하이드로겔, 이들의 제조 방법, 및 상기한 하이드로겔을 포함하는 조직 재생용 조성물에 관한 것이다. The present invention relates to acrylated hyaluronic acid derivatives or salts thereof, hydrogels prepared using the same, methods for their preparation, and compositions for tissue regeneration comprising the hydrogels described above.

하이드로겔은 조직공학 및 약물 전달 분야에서 널리 사용되는 물질로서, 하이드로겔에 약물 및 세포를 함께 포함시켜 조직 재생에 사용되고 있다.　 종래에는 하이드로겔을 사용하여 지지체를 제조하여 왔으며, 생체 활성이 좋으며 생체에 적용하기 용이한 주사형 지지체의 개발이 다양하게 시도되어 왔다. Hydrogel is a widely used material in the field of tissue engineering and drug delivery, and is used for tissue regeneration by incorporating drugs and cells in the hydrogel. Conventionally, a support has been prepared using a hydrogel, and various attempts have been made to develop an injectable support having good bioactivity and easy application to a living body.

조직 재생용 하이드로겔의 개발은 다양한 물질을 사용하여 다양한 방법으로 수행되어 왔다.　 기본적으로 사용되는 물질은 생체 적합성이 좋은 것으로 알려진 고분자로 PEG 등이 사용되어져 왔으나, 생체 외에서 유래한 물질들은 여러 가지 한계점을 가지고 있다. Development of hydrogels for tissue regeneration has been carried out in a variety of ways using a variety of materials. Basically, the material used is a polymer known to have good biocompatibility, and PEG has been used. However, materials derived from outside have various limitations.

생체 내 물질을 사용하여 조직공학용 지지체를 만드는 시도들이 행해져 왔으며, 그 중의 하나가 히알루론산 (Hyaluronic acid)을 이용하는 방법이다. Attempts have been made to create scaffolds for tissue engineering using in vivo materials, one of which uses hyaluronic acid.

히알루론산은 연골 및 연조직에 넓게 퍼져있는 생체 내 물질로, 생체 적합성이 좋으며 단일 체인으로 구성되어 있는 고분자로서, 면역반응이 없는 비부착성 글리코사민글리칸이다.　 세포의 표면물질과 반응을 하여 세포의 생장 및 분화를 조절하는 능력도 가지고 있어, 조직공학 및 약물전달용 물질로 사용되어 왔다. Hyaluronic acid is a biomaterial that is widely distributed in cartilage and soft tissues. It is a biocompatible, polymer composed of a single chain, and is non-adhesive glycosamine glycan with no immune response. It also has the ability to control cell growth and differentiation by reacting with surface material of cells, and has been used for tissue engineering and drug delivery.

히알루론산은 일작용성 및 다작용성 하이드라지드를 이용하여 화학적으로 변형이 시키거나 (Prestwich, G.D., et al., Controlled chemical modification of hyaluronic acid : synthesis, applications , and biodegradation of hydrazide derivatives . J Control Release, 1998. 53(1-3): p. 93-103.), 메타크릴레이트 그룹을 이용하여 변형시키거나 (Park, Y.D., N. Tirelli, and J.A. Hubbell, Photopolymerized hyaluronic acid - based hydrogels and interpenetrating networks . Biomaterials, 2003. 24(6): p. 893-900.과 Baier Leach, J., et al., Photocrosslinked hyaluronic acid hydrogels : Natural , biodegradable tissue engineering scaffolds . Biotechnol Bioeng, 2003. 82(5): p. 578-89.), 아미노 또는 알데하이드를 이용하여 변형시킨 바 있다 (Bulpitt, P. and D. Aeschlimann, New strategy for chemical modification of hyaluronic acid : preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res, 1999. 47(2): p. 152-69.).　 이렇게 변형된 히알루론산을 이용하여 많은 연구자들은 새로운 지지체를 만들었으며, Leach 등 (Leach, J.B. and C.E. Schmidt, Characterization of protein release from photocrosslinkable hyaluronic acid - polyethylene glycol hydrogel tissue engineering scaffolds . Biomaterials, 2005. 26(2): p. 125-35.)은 분해속도를 조절하고, BSA(bovine serum albumin)를 분비하는 글리시딜 메타크릴레이트-히알루론산 (GMHA) 하이드로겔을 만들었다. 또한, Kisiday 등 (Kisiday, J., et al., Self - assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division : implications for cartilage tissue repair . Proc Natl Acad Sci U S A, 2002. 99(15): p. 9996-10001.)은 연골 재생을 위한 펩타이드 수화겔 내에 연골세포를 넣는 기술을 개발하여 자가 조합의 펩타이드 수화겔 지 지체를 만들었다.　 그러나, 기존의 수화겔 지지체들은 교차결합 반응속도가 빠르지 못하고, 주사 주입이 가능하지 못했다. Hyaluronic acid can be chemically modified using mono- and polyfunctional hydrazides (Prestwich, G.D., et al.,Controlled chemical modification of hyaluronic acid synthesis, applications , and biodegradation of hydrazide derivatives . J Control Release, 1998.53(1-3): p. 93-103.) Or by using methacrylate groups (Park, Y.D., N. Tirelli, and J.A. Hubbell,Photopolymerized hyaluronic acid - based hydrogels and interpenetrating networks . Biomaterials, 2003.24(6): p. 893-900. And Baier Leach, J., et al.,Photocrosslinked hyaluronic acid hydrogels : Natural , biodegradable tissue engineering scaffolds . Biotechnol Bioeng, 2003.82(5): p. 578-89.), With amino or aldehydes (Bulpitt, P. and D. Aeschlimann,New strategy for chemical modification of hyaluronic acid : preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res, 1999.47(2): p. 152-69.). Using this modified hyaluronic acid, many researchers have made new scaffolds, including Leach et al. (Leach, J. B. and C. E. Schmidt,Characterization of protein release from photocrosslinkable hyaluronic acid - polyethylene glycol hydrogel tissue engineering scaffolds . Biomaterials, 2005.26(2): p. 125-35.) Produced glycidyl methacrylate-hyaluronic acid (GMHA) hydrogels that regulate the rate of degradation and secrete bovine serum albumin (BSA). In addition, Kisiday et al. (Kisiday, J., et al.,Self - assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division : implications for cartilage tissue repair . Proc Natl Acad Sci U S A, 2002.99(15): p. 9996-10001.) Developed a technique for inserting chondrocytes into peptide hydrogel for cartilage regeneration to create a self-combining peptide hydrogel retardation. However, the existing hydrogel supports do not have a fast crosslinking reaction rate and are not capable of injection injection.

이러한 배경 하에서, 본 발명자는 히알루론산을 기초한 생체적합성이 높은 생분해성 하이드로겔을 제조하고자 하였다.　 본 발명의 신규한 히알루론산 유도체는 생체와 같은 환경에서 가교결합제에 의해 수분 내에 겔을 형성하며, 이를 생체 내 주사함으로써 손상된 부위를 절개하는 등의 조처 없이도 조직이 재생되는 것을 확인하여 본 발명을 완성하였다. Under this background, the present inventors have attempted to produce highly biocompatible biodegradable hydrogels based on hyaluronic acid. The novel hyaluronic acid derivative of the present invention forms a gel in a few minutes by a crosslinking agent in an environment such as a living body, and completes the present invention by confirming that the tissue is regenerated without injecting the damaged area by injecting it in vivo. It was.

따라서, 본 발명의 목적은 히알루론산을 이용하여 생체적합성이 높은 생분해성 하이드로겔 및 생체 내 환경에서 겔화될 수 있어 손상된 조직에 바로 적용이 가능한 조직 재생용의 주사형 하이드로겔을 제공하는 것이다. Accordingly, an object of the present invention is to provide a biocompatible biodegradable hydrogel using hyaluronic acid and an injectable hydrogel for tissue regeneration that can be gelled in an in vivo environment and can be directly applied to damaged tissue.

본 발명자는 생체적합성이 높은 생분해성 하이드로겔을 개발하기 위해 생체 내 고분자인 히알루론산을 사용하였으며, 체내 환경에서 하이드로겔이 만들어지도록 하기 위하여, 히알루론산을 변형하였다. The present inventors used hyaluronic acid, a polymer in vivo, to develop a biodegradable hydrogel having high biocompatibility, and modified hyaluronic acid to make a hydrogel in the body environment.

하나의 양태로서, 본 발명은 하기 화학식 1의 아크릴화된 히알루론산 유도체 또는 이의 염에 관한 것이다: In one embodiment, the present invention relates to an acrylated hyaluronic acid derivative of Formula 1 or a salt thereof:

Figure 112006000286286-PAT00001
Figure 112006000286286-PAT00001

상기식에서, R은

Figure 112006000286286-PAT00002
이고, n은 4 내지 8이다.Wherein R is
Figure 112006000286286-PAT00002
And n is 4 to 8.

치환기 R에서 n은 바람직하게는 4이다.N in the substituent R is preferably 4.

본원에 사용된 히알루론산은, 특별히 제한되지는 않으나, 일반적으로 천연 물질, 바람직하게는 척추동물 또는 미생물로부터 유래되는 것을 사용할 수 있다.　 히알루론산의 분자량은 통상적으로 400,000 내지 10,000,000, 바람직하게는 600,000 내지 6,000,000 이다.　 히알루론산의 카복실 그룹의 형태는 염의 형태를 취할 수 있으며, 이러한 경우 알칼리 금속염, 또는 알칼리 토금속염의 형태일 수 있다.　 이러한 염은 나트륨염 또는 칼륨염이 바람직하다. As used herein, hyaluronic acid is not particularly limited, but may be generally used from a natural substance, preferably derived from a vertebrate or a microorganism. The molecular weight of hyaluronic acid is usually 400,000 to 10,000,000, preferably 600,000 to 6,000,000. The form of the carboxyl group of hyaluronic acid may take the form of a salt, in which case it may be in the form of an alkali metal salt, or an alkaline earth metal salt. Such salts are preferably sodium salts or potassium salts.

히알루론산은 조직으로부터 추출하거나 생합성될 수 있으며, 이와 관련한 많은 선행 문헌이 공지되어 있다 (대한민국 특허 출원 10-1987-0014225　 (1987.12.12), 10-1989-0009566　 (1989.07.06), 10-1985-0003599　 (1985.05.24)).　 예를 들어, 조직으로부터 추출하는 경우에는 닭의 볏, 관절의 활액, 사람 탯줄 조직, 소 기관지 등으로부터 추출할 수 있으며, 미생물로부터 얻는 경우에는 비용혈성 스트렙토코커스 속에 속하는 미생물을 배양하여 수득할 수 있다.　 Hyaluronic acid can be extracted or biosynthesized from tissues, and many prior documents are known in this regard (Korean Patent Application No. 10-1987-0014225 (1987.12.12), 10-1989-0009566 (1989.07.06), 10-1985 -0003599 '' (May 24, 1985). For example, when extracted from the tissue can be extracted from chicken crest, joint synovial fluid, human umbilical cord tissue, bovine bronchus, etc., if obtained from the microorganism can be obtained by culturing the microorganism belonging to the genus non-hemostatic Streptococcus. .

또 다른 양태로서, 본 발명은 In another aspect, the present invention

a) 히알루론산을 중합화제의 존재 하에 화학식 2의 디아민과 반응시키는 단계 및 a) reacting hyaluronic acid with a diamine of formula (2) in the presence of a polymerizing agent and

b) 단계 a)에서 얻어진 생성물을 아크릴화제와 반응시키는 단계를 포함하여, 화학식 1의 히알루론산 유도체 또는 이의 염을 생성하는 방법에 관한 것이다: b) a method of producing a hyaluronic acid derivative of formula (1) or a salt thereof, comprising reacting the product obtained in step a) with an acrylated agent:

화학식 1 Formula 1

Figure 112006000286286-PAT00003
Figure 112006000286286-PAT00003

Figure 112006000286286-PAT00004
Figure 112006000286286-PAT00004

상기식에서, R은

Figure 112006000286286-PAT00005
이고, n은 4 내지 8이다.Wherein R is
Figure 112006000286286-PAT00005
And n is 4 to 8.

치환기 R에서 n은 바람직하게는 4이다. N in the substituent R is preferably 4.

상기한 방법은 히알루론산의 COOH 그룹에 아크릴 그룹을 유도하기 위해 2 단계 공정을 이용하였다.　 하나의 구체적 양태로서, 하기 반응식 1을 예로 들어 설명하고자 한다. The method used a two step process to induce an acrylic group to the COOH group of hyaluronic acid. As one specific embodiment, the following Scheme 1 will be described as an example.

히알루론산의 아크릴화 Acrylated hyaluronic acid

Figure 112006000286286-PAT00006
Figure 112006000286286-PAT00006

먼저, 상온에서 히알루론산(0.25 mmole; 반복 단위 MW에 기초함)을 증류수에 녹여 중합반응제인 EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodimide)의 존재 하에 아디프산 디하이드라지드와 반응시킨다. 이어서, 아민 그룹이 유도된 히알루론산에 포름아마이드에 녹인 N-아크릴옥시숙신이미드 (N-acryloxysuccinimide)와 상온에서 반응시켜 최종적으로 아크릴 그룹이 도입된 히알루론산 유도체를 제조한다.　 상기 반응에서 중합반응제로는 커플링제인EDC와 함께 촉매제인 HOBT (0.17g, 1.25 mmole) 등이 사용 가능하다. 상기한 반응에서, N-아크릴옥시숙신이미드는 아크릴화제로 사용된다. First, hyaluronic acid (0.25 mmole; based on the repeating unit MW) is dissolved in distilled water at room temperature to adipic acid dihydrazide and adipic acid dihydrazide in the presence of the polymerization reagent EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodimide). React. Subsequently, N-acryloxysuccinimide dissolved in formamide is dissolved in hyaluronic acid derived from an amine at room temperature to prepare a hyaluronic acid derivative in which an acryl group is finally introduced. In the reaction, as a polymerization reagent, HOBT (0.17 g, 1.25 mmole) and the like may be used together with the coupling agent EDC. In the above reaction, N-acryloxysuccinimide is used as the acrylate agent.

또 다른 양태로서, 본 발명은 상기한 히알루론산 유도체 또는 이의 염을 티올 그룹을 갖는 가교결합제로 가교결합시킨 하이드로겔에 관한 것이다. In another aspect, the present invention relates to a hydrogel in which the hyaluronic acid derivative or salt thereof is crosslinked with a crosslinking agent having a thiol group.

바람직하게는, 티올 그룹을 갖는 가교결합제는 티올레이티드 폴리(에틸렌 글리콜), 티올 그룹이 있는 펩타이드 등 이다. Preferably, the crosslinker having a thiol group is a thiolated poly (ethylene glycol), a peptide with a thiol group, and the like.

보다 바람직하게는, 티올 그룹을 갖는 가교결합제는 화학식 3의 그룹이다: More preferably, the crosslinker having a thiol group is a group of formula 3:

Figure 112006000286286-PAT00007
Figure 112006000286286-PAT00007

빛에 의해 겔 제작이 가능한 히알루론산-기초된 하이드로겔을 폴리(에틸렌 글리콜)디아크릴레이트를 가교결합제로 이용하여　제작한 바 있었으나, 본 발명은 광중합 하에서가 아닌 미카엘 타입 부가 반응 (Michael type addition reaction) 반응을 이용하여, 생체 내에서도 하이드로겔을 형성이 가능한 주사형 하이드로겔을 제조하였다. Although hyaluronic acid-based hydrogels, which can be gelled by light, have been prepared using poly (ethylene glycol) diacrylate as a crosslinking agent, the present invention is a Michael type addition reaction, not under photopolymerization. By using the reaction, an injection hydrogel capable of forming a hydrogel in vivo was prepared.

또 다른 양태로서, 본 발명은 상기한 히알루론산 유도체 또는 이의 염을 티올 그룹을 갖는 가교결합제와 미카엘 부가 반응시켜 하이드로겔을 생성하는 방법에 관한 것이다. In another aspect, the present invention relates to a method for producing a hydrogel by reacting the hyaluronic acid derivative or a salt thereof with a Michael crosslinking agent with a thiol group.

생체 내의 반응 조건에서 겔이 만들어지도록 하기 위해 아크릴 그룹과 특이적으로 반응하는 티올 그룹이 있는 다양한 고분자 물질과 반응시켰다.　 바람직하게는, 티올 그룹이 있는 폴리(에틸렌 글리콜), 티올 그룹이 있는 펩타이드를 사용할 수 있다. In order to make the gel in the reaction conditions in vivo, it was reacted with various polymer materials having thiol groups that specifically reacted with acrylic groups. Preferably, poly (ethylene glycol) with thiol groups, peptides with thiol groups can be used.

상기 방법에서, 티올 그룹을 갖는 가교결합제는 보다 바람직하게는 상기 화학식 3의 그룹이다. In this method, the crosslinking agent having a thiol group is more preferably a group of formula (3).

하나의 구체적 양태로서, 하기 반응식 2을 예로 들어 설명하고자 한다. As one specific embodiment, the following Scheme 2 will be described as an example.

아크릴화된 히알루론산의 티올 가교결합제를 이용한 하이드로겔 제조  Hydrogel Preparation Using Thiol Crosslinkers of Acrylated Hyaluronic Acid

Figure 112006000286286-PAT00008
Figure 112006000286286-PAT00008

상기 겔 형성 반응은 아크릴화된 히알루론산을 트리에탄올아민-완충된 용액 (TEA)에 녹여 1% (w/v)용액을 만들고 티올 그룹을 갖는 가교결합제인 티올 그룹이 들어간 다양한 분자를 아크릴 그룹과 티올 그룹의 몰비가 1:1이 되게 넣어주어 37℃ 조건 하에서 반응시킨다. The gel-forming reaction was performed by dissolving acrylated hyaluronic acid in a triethanolamine-buffered solution (TEA) to form a 1% (w / v) solution and adding various molecules containing a thiol group, a crosslinking agent having a thiol group, to an acrylic group and a thiol group. The molar ratio of 1 is 1: 1 and reacted under 37 ℃ conditions.

또 다른 양태로서, 본 발명은 상기한 하이드로겔을 포함하는 조직 재생 또는 재흡착 방지용 조성물에 관한 것이다. In still another aspect, the present invention relates to a composition for preventing tissue regeneration or resorption comprising the hydrogel.

상기 조성물은 티올 그룹이 있는 다양한 화합물 중에서 선택된 바이오분자(biomolecule)를 추가로 포함할 수 있으며, 그 예로서 매트릭스 메탈로 프로테아제 에 의해 분해되는 서열을 가진 펩타이드, 플라스민에 의해 분해되는 서열을 가진 펩타이드 등을 포함한다.The composition may further comprise a biomolecule selected from various compounds having a thiol group, for example, a peptide having a sequence degraded by a matrix metalloprotease, a peptide having a sequence degraded by plasmin And the like.

또한, 본 발명의 상기한 히알루론산 유도체/히알루론산-기초된 하이드로겔은 본원 발명 이전에 공지된 모든 이용에 적용할 수 있으며, 구체적으로 바이오메디칼 물질, 예를 들어 조직재생용 지지체 (예를 들어, 손상 조직 삽입물, 성형 보조물), 약물 전달체; 항접착제 (예를 들어, 수술 동안 또는 수술 후 재흡착 방지제); 관절액, 초자체액 대용물 등으로 사용할 수 있다. In addition, the hyaluronic acid derivatives / hyaluronic acid-based hydrogels of the present invention can be applied to all uses known before the present invention, and specifically, biomedical materials such as a support for tissue regeneration (e.g., , Damaged tissue inserts, molding aids), drug carriers; Antiadhesives (eg, antiadhesion agents during or after surgery); It can be used as a joint fluid, vitreous fluid substitute, and the like.

바람직하게는, 상기 조성물은 조직 재생을 위해 사용할 수 있으며, 그 예로는 세포치료법과 병행하여 신경 재생, 심장 재생. 경조직 재생 등에 사용 가능하다. Preferably, the composition can be used for tissue regeneration, such as nerve regeneration, cardiac regeneration in combination with cell therapy. It can be used for hard tissue regeneration.

또 다른 양태로서, 본 발명은 상기한 히알루론산 유도체 또는 이의 염 및 티올 그룹을 갖는 가교결합제를 포함하는, 주사가능한 하이드로겔 생성 조성물에 관한 것이다. In another aspect, the present invention relates to an injectable hydrogel generating composition comprising a crosslinking agent having a hyaluronic acid derivative or a salt thereof and a thiol group as described above.

본 발명에 따라 제조된 히알루론산 유도체는 생체 내에 주사하여 히알루론산-기초된 하이드로겔을 생성할 수 있어 뼈, 신경 등 결손된 조직에 최소의 손상을 주고 이들 결손된 조직을 재생하는데 사용할 수 있다.　 Hyaluronic acid derivatives prepared according to the present invention can be injected in vivo to produce hyaluronic acid-based hydrogels that can be used to regenerate these defective tissues with minimal damage to bone, nerve, and other tissues.

상기 조성물에는　다양한 바이오분자를 첨가할 수 있어, 이들 물질들의 활성이 유지된 채로 생체 내 전달이 가능하다Various biomolecules can be added to the composition, thereby enabling in vivo delivery while maintaining the activity of these substances.

이하, 실시예를 들어 본 발명은 보다 구체적으로 설명하고자 한다.　 그러나, 본 발명이 이들 구체적 예로 한정되는 것은 아니며, 이는 단지 설명을 위한 것으로 간주되어야 하며, 첨부된 특허청구범위의 범위 내에서 다양한 변형이 가능하다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these specific examples, which should be regarded as merely illustrative, and various modifications are possible within the scope of the appended claims.

실시예Example

제조실시예Preparation Example 1: 히알루론산 유도체의 제조 1: Preparation of hyaluronic acid derivative

히알루론산 (Lifecore Biomedical Co. (Chaska, MN, USA))을 증류수 40 ml에 녹여 0.25 mmole을 만든 후, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodimide) (Sigma-Aldrich Inc, (St. Louis. MO. USA) (0.24g, 1.25 mmole)의 존재 하에 아디프산 디하이드라지드 (Fluka Chemical Co. (Buchs, Switzerland) (2.2 g, 12. 5 mmole)와 반응시키고, 아민 그룹이 유도된 히알루론산에 포름아마이드에 녹인 N-아크릴옥시숙신이미드 (Polyscience Inc, (Sarrington, PA, USA) (0.5 g, 3 mmole)와 상온에서 1 시간 동안 반응시켰다. 이어서, 반응물을 투석 분리하여 동결 건조하고 최종적으로 아크릴 그룹이 도입된 히알루론산 유도체를 제조하였다. 아크릴화된 히알루론산은 FT-IR 분광학 (도 2)과 1H-NMR로 확인하였다. After dissolving hyaluronic acid (Lifecore Biomedical Co. (Chaska, MN, USA)) in 40 ml of distilled water to make 0.25 mmole, EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodimide) (Sigma-Aldrich Inc, (St Reacted with adipic acid dihydrazide (Fluka Chemical Co. (Buchs, Switzerland) (2.2 g, 12. 5 mmole)) in the presence of Louis.MO.USA) (0.24 g, 1.25 mmole). Induced hyaluronic acid was reacted with N-acryloxysuccinimide (Polyscience Inc, (Sarrington, PA, USA) (0.5 g, 3 mmole) dissolved in formamide for 1 hour at room temperature. Hyaluronic acid derivatives were lyophilized and finally introduced with acrylic groups, and acrylated hyaluronic acid was identified by FT-IR spectroscopy (FIG. 2) and 1 H-NMR.

제조 Produce 실시예Example 2:  2: 하이드로겔의Hydrogel 제조 Produce

겔 형성 반응은 아크릴화된 히알루론산을 트리에탄올아민-완충 용액 (TEA; 0.3M, pH 8)에 녹여 1% (w/v)용액을 만들고 티올 그룹을 갖는 가교결합제인 티올레이티드 폴리(에틸렌 글리콜)을 아크릴 그룹과 티올 그룹의 몰비가 1:1이 되게 넣어주어 37℃ 조건 하에서 반응시켜 제조하였다. The gel forming reaction dissolves acrylated hyaluronic acid in triethanolamine-buffered solution (TEA; 0.3M, pH 8) to form a 1% (w / v) solution and is a thiolated poly (ethylene glycol) crosslinker with thiol groups. The molar ratio of acryl group and thiol group was put to 1: 1 to prepare a reaction under 37 ℃ conditions.

실험실시예Laboratory 1:  One: 하이드로겔의Hydrogel 형성 속도 측정 Formation rate measurement

히알루론산-기초된 하이드로겔은 생체와 같은 환경 (37℃, pH 7.4)에서 수분 내에 겔이 만들어지는 것을 확인하였으며, 완전하게 하이드로겔 반응이 되는 것은 30분 이내임을 확인하였다 (도 3). 하이드로겔 반응 속도는 Rotational Rheometer Gemini (Bohlin Instruments Ltd., Germany)를 사용하여 측정하였다. 1 ml의 아크릴화된 히알루론산과　 티올레이티드 폴리(에틸렌 글리콜) 용액을 샌드블라스트 평형 플레이트 (sandblast parallel plate; 직경 15 mm) 위에 올려놓고, 37°C, 500um 갭, 0.1 % 스트레인의 타임 스윕 (time sweep)　 측정을 하였고, 0.1 내지 10 rad/s, strain at 0.1% at 20°C에서 frequency sweep 측정을 하였다. 젤이 완전히 형성 된 후, 점성 계수와 탄성 계수를 1 시간 동안 관찰하여 확인한 결과 170 Pa, 2800 Pa로 나타났다.The hyaluronic acid-based hydrogel was confirmed that the gel is formed within a few minutes in the same environment as the living body (37 ℃, pH 7.4), it was confirmed that the complete hydrogel reaction within 30 minutes (Fig. 3). Hydrogel reaction rate was measured using a Rotational Rheometer Gemini (Bohlin Instruments Ltd., Germany). 1 ml of acrylated hyaluronic acid and thiolated poly (ethylene glycol) solution is placed on a sandblast parallel plate (15 mm in diameter), time sweep of 37 ° C, 500um gap, 0.1% strain sweep) was measured, and the frequency sweep was measured at 0.1 to 10 rad / s, strain at 0.1% at 20 ° C. After the gel was completely formed, the viscosity coefficient and the elastic modulus were observed for 1 hour and found to be 170 Pa, 2800 Pa.

실험실시예Laboratory 2:  2: 하이드로겔의Hydrogel 분해 속도 측정 Decomposition Rate Measurement

히알루론산-기초된 하이드로겔이 히알루로니다제에 의해 분해되는 양상을 확인하기 위하여 하이드로겔의 조성을 변경하면서 실험한 결과 (아크릴화된 히알루론산과　 티올레이티드 폴리(에틸렌 글리콜)의 몰 비율이 (A) 1:1, (B) 1:2, (C) 1:4 즉, (A)의 경우에는 아크릴화된 히알루론산 10mg을 TEA (0.3M, pH 8)에 녹여 1% (w/v)로 만든 용액에 티올레이티드 폴리(에틸렌 글리콜) 30mg을 넣어주었고, (B)의 경우에는 아크릴화된 히알루론산 10mg을 TEA (0.3M, pH 8)에 녹여 1% (w/v)로 만든 용액에 티올레이티드 폴리(에틸렌 글리콜) 60mg을 넣어주었고, (C)의 경우에는 아크릴화된 히알루론산 10mg을 TEA (0.3M, pH 8)에 녹여 1% (w/v)로 만든 용액에 티올레이티드 폴리(에틸렌 글리콜) 120mg을 넣어주었다. 히알루론산의 조성이 높은 샘플 (A)의 분해가 가장 많이 되는 것으로 확인되었으며, 조성비가 가장 낮은 샘플 (B)의 경우 분해가 느린 것을 확인할 수 있었다 (도 4). In order to confirm the dissolution of hyaluronic acid-based hydrogels by hyaluronidase, experiments were carried out with changing the composition of the hydrogels (the molar ratio of acrylated hyaluronic acid and thiolated poly (ethylene glycol) was (A ) 1: 1, (B) 1: 2, (C) 1: 4, i.e. (A), 10 mg of acrylated hyaluronic acid was dissolved in TEA (0.3M, pH 8) to 1% (w / v) 30 mg of thiolated poly (ethylene glycol) was added to the solution, and in case of (B), 10 mg of acrylated hyaluronic acid was dissolved in TEA (0.3M, pH 8) to thiol in a solution made of 1% (w / v). 60 mg of laminated poly (ethylene glycol) was added, and in the case of (C), 10 mg of acrylated hyaluronic acid was dissolved in TEA (0.3M, pH 8) to make 1% (w / v) of thiolated poly ( Ethylene glycol) was added 120 mg of hyaluronic acid was found to be the most degraded sample (A). If the ratio of the lowest sample (B) it was confirmed that decomposition is slow (FIG. 4).

실험실시예Laboratory 3:  3: 하이드로겔의Hydrogel 경조직Hard tissue 재생 효과 Play effect

하이드로겔을 제작할 때에, 사람의 중간엽줄기세포와 500 ng의 BMP (bone morphogenic protein)-2 (R&D Systems)를 첨가하였으며, 모델 시스템으로는 carvarial 결손 래트 (Male Sprague Dawley albino rats)를 사용하였다. 도 5는 조직 재생에 대한 결과를 보이는 Masson 삼색 염색에 따른 조직화학염색사진이다.　 도 5a는 히알루론산 하이드로겔, 도 5b는 히알루론산 하이드로겔 + BMP-2, 도 5c는 히알루론산 하이드로겔 + 줄기 세포, 도 5d는 히알루론산 하이드로겔 + 스템 세포 + BMP-2에 대한 것이다.　 줄기 세포와 BMP를 첨가한 샘플에서 골 형성이 가장 우수하였다.　 또한, 4주 이내에 하이드로겔이 생체 내에서 분해되는 것을 확인하였으며, 다른 염증 등의 부작용은 관찰되지 않았다. In the preparation of the hydrogel, human mesenchymal stem cells and 500 ng of BMP (bone morphogenic protein) -2 (R & D Systems) were added, and a carvarial-deficient rat (Male Sprague Dawley albino rats) was used as a model system. Figure 5 is a histochemical staining picture according to Masson tricolor staining showing the results for tissue regeneration. Figure 5a is a hyaluronic acid hydrogel, Figure 5b is a hyaluronic acid hydrogel + BMP-2, Figure 5c is a hyaluronic acid hydrogel + stem cells, Figure 5d is a hyaluronic acid hydrogel + stem cells + BMP-2. Bone formation was the best in the sample added with stem cells and BMP. In addition, it was confirmed that hydrogels are degraded in vivo within 4 weeks, and no side effects such as inflammation were observed.

본 발명에 따라 제조된 히알루론산 유도체는 생체 내에 주사하여 히알루론산-기초된 하이드로겔을 생성할 수 있어 뼈, 신경 등 결손된 조직에 최소의 손상을 주고 이들 결손된 조직을 재생하는데 사용할 수 있다.　 또한, 다양한 바이오분자를 첨가할 수 있어, 이들 물질들의 활성이 유지된 채로 생체 내 전달이 가능하다. 또한, 히아루론산-기초된 하이드로겔은 바이오메디칼 물질, 예를 들어 항접착제 (예를 들어 수술 동안 또는 후 재흡착 방지) 등으로 사용할 수 있다. Hyaluronic acid derivatives prepared according to the present invention can be injected in vivo to produce hyaluronic acid-based hydrogels that can be used to regenerate these defective tissues with minimal damage to bone, nerve, and other tissues. In addition, various biomolecules can be added, allowing for in vivo delivery while maintaining the activity of these materials. In addition, hyaluronic acid-based hydrogels can be used as biomedical materials such as antiadhesives (eg, to prevent readsorption during or after surgery) and the like.

Claims (15)

하기 화학식 1의 아크릴화된 히알루론산 유도체 또는 이의 염.An acrylated hyaluronic acid derivative of Formula 1 or a salt thereof. 화학식 1 Formula 1
Figure 112006000286286-PAT00009
Figure 112006000286286-PAT00009
 상기식에서, R은
Figure 112006000286286-PAT00010
이고, n은 4 내지 8이다.Wherein R is
Figure 112006000286286-PAT00010
And n is 4 to 8. 제1항에 있어서, n이 4인 히알루론산 유도체 또는 이의 염. The hyaluronic acid derivative according to claim 1, or a salt thereof, wherein n is 4. 4. a) 히알루론산을 중합화제의 존재 하에 화학식 2의 디아민과 반응시키는 단계 및 b) 단계 a)에서 얻어진 생성물을 아크릴화제와 반응시키는 단계를 포함하여, 화학식 1의 히알루론산 유도체 또는 이의 염을 생성하는 방법. a) reacting hyaluronic acid with a diamine of formula (2) in the presence of a polymerizing agent and b) reacting the product obtained in step a) with an acrylate agent to produce a hyaluronic acid derivative of formula (1) or a salt thereof Way. 화학식 1 Formula 1
Figure 112006000286286-PAT00011
Figure 112006000286286-PAT00011
 화학식 2 Formula 2
Figure 112006000286286-PAT00012
Figure 112006000286286-PAT00012
 상기식에서, R은
Figure 112006000286286-PAT00013
이고, n은 4 내지 8이다.Wherein R is
Figure 112006000286286-PAT00013
And n is 4 to 8. 제3항에 있어서, 아크릴화제가 N-아크릴옥시숙신이미드인 방법. The method of claim 3 wherein the acrylated agent is N-acryloxysuccinimide. 제1항의 히알루론산 유도체 또는 이의 염을 티올 그룹을 갖는 가교결합제로 가교결합시킨 하이드로겔. A hydrogel in which the hyaluronic acid derivative of claim 1 or a salt thereof is crosslinked with a crosslinking agent having a thiol group. 제5항에 있어서, 티올 그룹을 갖는 가교결합제가 티올레이티드 폴리에틸렌 글리콜 또는 티올 그룹이 있는 펩타이드인 하이드로겔. 6. The hydrogel of claim 5, wherein the crosslinker having a thiol group is a thiolated polyethylene glycol or a peptide with a thiol group. 제6항에 있어서, 티올 그룹을 갖는 가교결합제가 화학식 3의 그룹인 하이드로겔. 7. The hydrogel of claim 6, wherein the crosslinker having a thiol group is a group of formula (3). 화학식 3 Formula 3
Figure 112006000286286-PAT00014
Figure 112006000286286-PAT00014
 제1항의 히알루론산 유도체 또는 이의 염을 티올 그룹을 갖는 가교결합제와 미카엘 부가 반응 (Michael addition reaction)시켜 하이드로겔을 생성하는 방법. The method of claim 1, wherein the hyaluronic acid derivative or a salt thereof is subjected to a Michael addition reaction with a crosslinking agent having a thiol group to generate a hydrogel. 제8항에 있어서, 티올 그룹을 갖는 가교결합제가 티올레이티드 폴리에틸렌 글리콜 또는 티올 그룹이 있는 펩타이드인 방법. The method of claim 8, wherein the crosslinker having a thiol group is a thiolated polyethylene glycol or a peptide with a thiol group. 제9항에 있어서, 티올 그룹을 갖는 가교결합제가 화학식 3의 그룹인 방법. The method of claim 9, wherein the crosslinker having a thiol group is a group of formula (3). 화학식 3 Formula 3
Figure 112006000286286-PAT00015
Figure 112006000286286-PAT00015
 제5항의 하이드로겔을 포함하는 조직 재생 또는 재흡착 방지용 조성물. A composition for preventing tissue regeneration or resorption comprising the hydrogel of claim 5. 제11항에 있어서, 매트릭스 메탈로 프로테아제 분해 펩타이드, 플라스민 분해 서열을 포함하는 펩타이드 중에서 선택된 바이오분자를 추가로 포함하는 조성물. The composition of claim 11, further comprising a biomolecule selected from a matrix metalloprotease cleavage peptide, a peptide comprising a plasmin cleavage sequence. 제1항의 히알루론산 유도체 또는 이의 염 및 티올 그룹을 갖는 가교결합제를 포함하는, 주사가능한 하이드로겔 생성 조성물. An injectable hydrogel generating composition comprising a crosslinking agent having a hyaluronic acid derivative of claim 1 or a salt thereof and a thiol group. 제13항에 있어서, 매트릭스 메탈로 프로테아제 분해 펩타이드, 플라스민 분해 서열을 포함하는 펩타이드 중에서 선택된 바이오분자를 추가로 포함하는 조성물. The composition of claim 13, further comprising a biomolecule selected from a matrix metalloprotease cleavage peptide, a peptide comprising a plasmin cleavage sequence. 제13항에 있어서, 조직 재생용인 조성물. The composition of claim 13, which is for tissue regeneration.
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