Chemical Approaches to Scaffold Creation for Tissue Engineering

Tissue-imitating scaffolds play an important role not only in tissue-engineering research but also in actual medical aplications. For example for treatment of severe burns. When seeded with mesenchymal stem cells (MSCs), such a MSCs/scaffold system can significantly accelerate healing, reduce fibrosis and scarring, promote angiogenesis and keratinization, and reduce inflammation [1-5]. Such scaffolds can also be seeded with dermal cells (dermal fibroblasts, keratinocytes, adipocytes, vascular endothelial cells, etc.) to create artificial skin for grafting [6-8]. It is especially relevant for burn victims with a large area of skin loss when there is not enough undamaged skin for an autograft [9]. 

The most obvious choice for the source of tissue scaffold would be natural scaffolds made from decellularized human or animal tissues. However, these natural scaffolds have several significant disadvantages. Recellularizing of previously decellularized tissues is a time-consuming, complicated process requiring donor tissue and expensive equipment. Donor tissue is expensive and very hard to obtain. Using animal tissue for this purpose can introduce to patients new zoonotic pathogens that could cause serious complications and hard to treat or even utreatbale diseases. In addition, such scaffolds also require special and expensive equipment to store and transport. Hence more inexpensive and reliable alternative is needed. 

Structure-wise scaffolds can be divided into two types. One type is “soft” scaffolds in the form of hydrogels. They are usually made of natural for the body materials, like polysaccharides (agar, chitosan, hyaluronic acid, pectins, alginate etc.) and proteins (collagen, fibrin etc.). Although hydrogel scaffolds also could be made from such biocompatible synthetic materials like polyethylene glycol (PEG), polyvinyl alcohol (PVA), and polyacrylic acid (PAA) [10-11]. The other type is “hard” scaffolds, which also could be divided into two sub-types: natural scaffolds from decellularized tissues (DTS - decellularized tissues scaffolds) [12], mentioned above, and manufactured scaffolds, made of biocompatible synthetic materials, such as polycaprolactone (PCL), or combination of synthetic and natural materials (f.e. Pectin-chitosan-PVA nanofibers). Manufactured scaffolds, in turn, can be divided into fibrous scaffolds and porous scaffolds [8, 13]. In comparison with DTS manufactured scaffolds have much better mechanical strength and are easy and inexpensive to fabricate, store, and transport [2]. Although they are not as good at imitating natural cell environment as DTS. 

Each of these scaffolds have their pros and cons. Although hydrogels have high porosity, the mesh size is quite small and might impede nutrient and gas exchange for the embedded cells [14]. Other disadvantages of using hydrogels as scaffolds include limited mechanical strength, lack of long-term stability, and limited control over their structure [15]. Fibrous scaffolds are often fabricated using a technique known as electrospinning. The main disadvantages of this method are the inability to have precise control over distances between fibers and the limited control required to achieve complex 3D structures. As a result, the non-cellular part of the scaffold material might take up a significant percentage of the whole cell/scaffold system, leaving only limited space for cells. 3D-printed porous scaffolds, on the other hand, allow for much better control over their structure, but the problem of a high percentage of the non-cellular scaffold material remains.

In conclusion, chose of specific scaffolds and the materials from which they are made will depend on such factors as their application, availability, and type of tissue/organ that they will be used to imitate. 

References

1. Zhao M, Kang M, Wang J, Yang R, Zhong X, Xie Q, Zhou S, Zhang Z, Zheng J, Zhang Y, Guo S, Lin W, Huang J, Guo G, Fu Y, Li B, Fan Z, Li X, Wang D, Chen X, Tang BZ, Liao Y. Stem Cell-Derived Nanovesicles Embedded in Dual-Layered Hydrogel for Programmed ROS Regulation and Comprehensive Tissue Regeneration in Burn Wound Healing. Adv Mater. 2024 Aug; 36(32):e2401369.
2. Abdul Kareem N, Aijaz A, Jeschke MG. Stem Cell Therapy for Burns: Story so Far. Biologics. 2021 Aug 31; 15:379-397.
3. Jo H, Brito S, Kwak BM, Park S, Lee MG, Bin BH. Applications of Mesenchymal Stem Cells in Skin Regeneration and Rejuvenation. Int J Mol Sci. 2021 Feb 27; 22(5):2410.
4. Francis E, Kearney L, Clover J. The effects of stem cells on burn wounds: a review. Int J Burns Trauma. 2019 Feb 15; 9(1):1-12.
5. Shumakov VI, Onishchenko NA, Rasulov MF, Krasheninnikov ME, Zaidenov VA. Mesenchymal bone marrow stem cells more effectively stimulate regeneration of deep burn wounds than embryonic fibroblasts. Bull Exp Biol Med. 2003 Aug; 136(2):192-5.
6. Ye Xu, Xiangyi Wu, Yuanyuan Zhang, Yunru Yu, Jingjing Gan, Qian Tan. Engineered artificial skins: Current construction strategies and applications. Engineered Regeneration. Volume 4, Issue 4. 2023, Pages 438-450
7. Lukomskyj AO, Rao N, Yan L, Pye JS, Li H, Wang B, Li JJ. Stem Cell-Based Tissue Engineering for the Treatment of Burn Wounds: A Systematic Review of Preclinical Studies. Stem Cell Rev Rep. 2022 Aug; 18(6):1926-1955.
8. Nokoorani YD, Shamloo A, Bahadoran M, Moravvej H. Fabrication and characterization of scaffolds containing different amounts of allantoin for skin tissue engineering. Sci Rep. 2021 Aug 9; 11(1):16164.
9. Rubis BA, Danikas D, Neumeister M, Williams WG, Suchy H, Milner SM. The use of split-thickness dermal grafts to resurface full thickness skin defects. Burns. 2002 Dec; 28(8):752-9.
10. Nikolova MP, Chavali MS. Recent advances in biomaterials for 3D scaffolds: A review. Bioact Mater. 2019 Oct 25; 4:271-292.
11. Bačáková L, Novotná K, Pařízek M. Polysaccharides as cell carriers for tissue engineering: the use of cellulose in vascular wall reconstruction. Physiol Res. 2014; 63(Suppl 1):S29-47.
12. Paramasivam T, Maiti SK, Palakkara S, Rashmi, Mohan D, Manjunthaachar HV, Karthik K, Kumar N. Effect of PDGF-B Gene-Activated Acellular Matrix and Mesenchymal Stem Cell Transplantation on Full Thickness Skin Burn Wound in Rat Model. Tissue Eng Regen Med. 2021 Apr; 18(2):235-251.
13. Lin HY, Chen HH, Chang SH, Ni TS. Pectin-chitosan-PVA nanofibrous scaffold made by electrospinning and its potential use as a skin tissue scaffold. J Biomater Sci Polym Ed. 2013; 24(4):470-84.
14. Li XJ, Valadez AV, Zuo P, Nie Z. Microfluidic 3D cell culture: potential application for tissue-based bioassays. Bioanalysis. 2012 Jun; 4(12): 1509-25.
15. Abuwatfa WH, Pitt WG, Husseini GA. Scaffold-based 3D cell culture models in cancer research. J Biomed Sci. 2024 Jan 14; 31(1):7.