인체이식용 무세포 진피 제조를 위한 바이러스 불활화 공정
Virus Inactivation Processes for the Manufacture of Human Acellular Dermal Matrix.
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초록
사체 피부에서 면역반응을 일으킬 수 있는 세포들을 제거한 무세포 진피는 다양한 의료용 소재로 사용되고 있다. Trin-butyl phospahate(TnBP)와 deoxycholic acids를 세포제거용액으로 사용하여 피부조직 내 진피층의 3차원적 구조를손상시키지 않고 다양한 구조 단백질 및 성분들을 유지한 상태에서 면역반응의 대상인 세포성 항원만을 선별적으로 제거한 이식용 동종 무세포 진피인 SureDermTM을 개발하였다. SureDermTM 제조공정은 감염성 위해인자 불활화 공정으로70% 에탄올 처리와 산화에틸렌 가스 처리 공정을 포함하고있다. 본 연구에서는 SureDermTM 제조공정 중 70% 에탄올소독 공정, 세포제거용액(0.1% TnBP와 2% deoxycholic acids) 처리 공정, 산화에틸렌 가스 멸균의 바이러스 불활화효과를 검증하기 위해 국제적 가이드에 따라 5종의 바이러스 [human immunodeficiency virus type 1(HIV-1), bovine herpes virus(BHV), Bovine viral diarrhoea virus(BVDV),hepatitis A virus(HAV), porcine parvovirus(PPV)]를 생물학적 지표로 사용하였다. 피부조직에 각 생물학적 지표를 첨가한 후 불활화 공정을 실시한 다음 각 바이러스를 회수하여 정량한 후 불활화 정도를 비교하였다. 70% 에탄올 20분처리 공정에서 HIV-1, BHV, BVDV 같은 외피 바이러스는처리 시간 2.5분 안에 불활화되었지만, HAV와 PPV 같은 비-외피 바이러스는 에탄올에 저항성을 나타내어 20분 처리 후log 바이러스 감소인수가 각각 1.85와 1.15였다. 세포제거용액 처리 공정에서 HIV-1, BHV, BVDV는 각각 5분, 30분,5분 안에 검출한계 이하로 불활화되었다. 산화에틸렌 가스처리에 의해 본 연구에 사용한 모든 바이러스가 검출한계 이하로 불활화되었다. 3가지 공정에서 HIV-1, BHV, BVDV,HAV, PPV에 대한 log 바이러스 감소인수 합은 각각≥12.71, ≥18.08, ≥14.92, ≥6.57, ≥7.18이었다. 이와 같은 결과에서 SureDermTM 제조공정은 바이러스 안전성을 보증할수 있는 충분한 바이러스 불활화 능력을 갖고 있는 것으로판단된다.
Abstract
Acellular dermal matrix (ADM), produced by decellularization from human cadaveric skin, has been used for various biomedical applications. A manufacturing process for ADM (SureDermTM) using tri-n-butyl phospahate (TnBP) and deoxycholic acids as the decellularization solution has been developed. The manufacturing process for SureDermTM has 70%ethanol treatment and ethylene oxide gas sterilization for inactivating infectious microorganisms. The purpose of this study was to examine the efficacy of the 70% ethanol treatment, decellularization process using 0.1%TnBP and 2% deoxycholic acids, and EO gas sterilization process in the inactivation of viruses. A variety of experimental model viruses for human pathogens, including the human immunodeficiency virus type 1 (HIV-1), bovine herpes virus (BHV), bovine viral diarrhoea virus (BVDV), hepatitis A virus (HAV), and porcine parvovirus (PPV) were all selected for this study. Enveloped viruses such as HIV-1, BHV, and BVDV were effectively inactivated to undetectable levels by 70% ethanol treatment. However HAV and PPV showed high resistance to 70% ethanol treatment with the log reduction factors of 1.85 and 1.15, respectively. HIV-1, BHV, and BVDV were effectively inactivated to undetectable levels by decellularization process. All the viruses tested were completely inactivated to undetectable levels by EO gas treatment. The cumulative log reduction factors of HIV-1, BHV, BVDV, HAV, and PPV were ≥12.71, ≥18.08, ≥14.92, ≥6.57, and ≥7.18, respectively. These results indicate that the production process for SureDermTM has a sufficient virus-reducing capacity to achieve a high margin of the virus safety.
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