The Cell-Assembled extracellular Matrix: a focus on the storage stability and terminal sterilization of this human “bio” material.

Tissue-Engineered Products (TEPs) offer groundbreaking opportunities in healthcare and are the subject of thousands of research studies around the world. However, only a handful of them have led to clinical trials and they have yet to achieve widespread clinical use. To date, only 102 clinical trials in tissue engineering have been conducted [1], and fewer than 20 TEPs have been approved or marketed [2]. This low rate of clinical translation can be explained by the important manufacturing and regulatory challenges [3] associated with TEP development. Some of these difficulties can bring a breakthrough technology to a standstill when they have not been addressed sufficiently early in the development process.

Our team has shown that the Cell-Assembled extracellular Matrix (CAM), produced by normal adult skin fibroblasts in vitro, is truly a “bio”-material with a strong therapeutic potential [4]. We have recently focused on the development of CAM-based human textiles as an innovative technology to produce TEPs [5]. In this study, we address two issues that are crucial for the development of any CAM-based TEP: product stability and sterilization.

Off-the-shelf availability is a key feature to facilitate clinical adoption and allow the use of the product in emergency cases. A critical limitation for the clinical relevance of TEP is often storage temperature. For example, while -80°C storage is readily available in academic research, this type of storage is challenging in a clinical context as the world recently experienced with the SARS-CoV-2 vaccines [6].

Sterility is an absolute requirement for TEP. Aseptic manufacturing is an option, and successful products have reached clinical trials and even commercialization (Dermagraft®, Apligraft®) using this strategy [7,8,9]. Although this process may be optimal, it comes at a significant cost in terms of time, complexity, infrastructure, risks, and quality control. Terminal sterilization is an alternative strategy that provides high safety levels, that are preferred by regulatory agencies, and simplifies manufacturing [10]. However, sterilization methods are known for altering biomaterials, particularly when they are of biological origin, resulting in changes in mechanical and chemical properties that can impair in vivo performance [11]. To date, no consensus exists on an appropriate sterilization protocol and sterilization effects must be evaluated on every new biomaterial [12].

The first objective of this study is to characterize the effects of storage conditions on the mechanical and physicochemical properties of the CAM in vitro after 1 year of storage. The second objective is to evaluate the effects of 6 sterilization methods on the mechanical, physicochemical and biological properties of the CAM in vitro and in vivo. This work will allow the selection of the most appropriate methods to manufacture terminally sterilized CAM-based TEPs that can be available off-the-shelf.

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