Freeze-Drying Process for the Fabrication of Collagen-Based Sponges as Medical Devices in Biomedical Engineering

Abstract

This paper presents a systematic review of a key sector of the much promising and rapidly evolving field of biomedical engineering, specifically on the fabrication of three-dimensional open, porous collagen-based medical devices, using the prominent freeze-drying process. Collagen and its derivatives are the most popular biopolymers in this field, as they constitute the main components of the extracellular matrix, and therefore exhibit desirable properties, such as biocompatibility and biodegradability, for in vivo applications. For this reason, freeze-dried collagen-based sponges with a wide variety of attributes can be produced and have already led to a wide range of successful commercial medical devices, chiefly for dental, orthopedic, hemostatic, and neuronal applications. However, collagen sponges display some vulnerabilities in other key properties, such as low mechanical strength and poor control of their internal architecture, and therefore many studies focus on the settlement of these defects, either by tampering with the steps of the freeze-drying process or by combining collagen with other additives. Furthermore, freeze drying is still considered a high-cost and time-consuming process that is often used in a non-optimized manner. By applying an interdisciplinary approach and combining advances in other technological fields, such as in statistical analysis, implementing the Design of Experiments, and Artificial Intelligence, the opportunity arises to further evolve this process in a sustainable and strategic manner, and optimize the resulting products as well as create new opportunities in this field.

Keywords: Artificial Intelligence; alignment; biomaterials; biomedical engineering; collagen; freeze drying; gelatin; medical devices; modeling.

Figure 1

(A) Phase diagram of water [35] and (B) schematic diagram of the temperature and pressure changes during the freeze-drying process [36].

Figure 2

Phase diagram of a hypothetical solute-solvent system [37].

Figure 3

Schematic representation of the heat and mass transfer phenomena during the primary drying stage of the freeze-drying process [modified from [53]].

Figure 4

(A) Schematic representation of the process for the fabrication of aligned collagen-based sponges [modified from [134]], (B) longitudinal microstructure of an aligned collagen-based nerve guide, and (C) transverse microstructure of an aligned collagen-based nerve guide (Scale bars: B,C = 200 μm) [24].

Figure 5

(A) Generic schematic representation of the beginning-to-end fabrication process for the collagen-based-additive freeze-dried sponges, (B) macro- and microstructure of the starting hydrogel, and (C) macro- and microstructure of the final freeze-dried sponge. Scale bars: B = 400 μm and C = 500 μm [B,C modified from [166]].

Figure 6

Scanning Electron Microscopy image of HELISTAT^® (Scale bar: ~200 μm) [182].

Figure 7

SEM image of GraftJacket™ matrix [192].

Figure 8

DoE workflow for the process optimization [194].

Figure 9

Schematic representation of the proposed optimization process for the fabrication of collagen-based sponges as medical devices in biomedical engineering [modified from [194]].