Tissue engineering combines the principles of cells, growth factors, and biomaterials to develop substitute tissues and promote endogenous regeneration . Tissue engineering, as well as cell and gene therapy, could be considered as regenerative medicine, which is now attainable as a novel curing strategy . Fabricating body tissues such as cornea or cartilage and organs like skin and bone by tissue engineering strategies would lead to shortening the transplant waiting list, which is extending every 15 minutes by adding a patient name .
Cartilage is a rubbery, stiff, and connective tissue that depicts a limited potential of self-regeneration due to the sparse cellularity, diminished production of the extracellular matrix (ECM), and lack of blood vessels and neural innervations [4, 5]. Cartilage tissue engineering is one of the most appealing areas among scientists and clinicians, as the demand for cartilage repair and replacement increases considerably. On the one hand, cartilage diseases grow, so does the need for engineered cartilage tissues. Also, the progress of a sedentary lifestyle causes more bone and cartilage disorders. On the other hand, current surgical treatments for cartilage injuries are not satisfactory. Therefore, there is a climbing demand for novel strategies to induce cartilage development . By introducing biocompatible polymers and hydrogels, combined with cells and growth factors for cartilage repair, regenerative medicine supplies an alternative solution . Hence, it is predictable that cartilage tissue engineering's upward trend would be amplified in the foreseeable future .
There has been a dramatic progression in cartilage engineering during recent years . Studies show that tissue engineering and regenerative medicine facilities were used to overcome cartilage diseases [9–11]. Atoufi et al.  produced an injectable thermosensitive Poly (N-isopropyl-acrylamide) /hyaluronic acid hydrogels containing various amounts of Chitosan-g-acrylic acid-coated poly (lactic-co-glycolic acid) (PLGA) micro and nanoparticles to facilitate the development of cartilage tissue. They claimed that due to the desired mechanical properties, high bioactivity, and sustainable drug release ability, the mentioned injectable hydrogel is a promising biomaterial for cartilage tissue engineering. Chen et al.  developed a porous scaffold prepared by gelatin groove fibers. They could obtain a considerable water absorption property of scaffolds as high as 1187%. In their study, scaffolds compressive mechanical property was also evaluated. Upon their results, the scaffold above demonstrated elastic behavior in wet mode and could bear 100 cycles compressive fatigue test. Moreover, the test of this type of cartilage scaffold was successful in promoting rat chondrocyte and bone marrow mesenchymal stem cells (BMSC) proliferation.
Meanwhile, Al-Sabah et al.  developed a composite of natural biopolymer derived from cellulose, which is Nano-cellulose, and sodium alginate. They aimed to obtain a novel ink for cartilage scaffold 3D printing. They studied the impact of various calcium chloride cross-linker concentrations and sterilization strategies on the structural and mechanical properties of Nano-cellulose-based hydrogels for cartilage scaffolds. These scaffolds were containing plant-derived cellulose Nano-fibrils, cellulose nanocrystals, or a blend of the two.
In addition to the biomaterial determination for scaffold preparation, accurately selecting of various available cells are vital [15, 16]. Chen et al.  studied the effect of utilizing diverse bone marrow-derived cell sources, including bone marrow concentrate (BMC) and BMSC for cartilage tissue engineering. The biological constructs containing BMC/BMSCs and articular tissue fragments were examined in vitro. Their results illustrated the biological constructs containing BMC and articular fragments contributed to immeasurable chondrogenesis. Therefore, it can be thought that BMC would be a potential candidate for a cell source for cartilage tissue engineering. Moreover, scientists studied the immune reaction and the degradation of the scaffold's fate in the cartilage engineering field [18–21].
Growth factors, a group of biologically active polypeptides produced by the body, could stimulate cellular division, growth, and differentiation . In articular cartilage, numerous growth factors work in consonance to regulate the development and homeostasis of articular cartilage throughout life . They offer promising treatments for enhanced development of cartilage in focal articular cartilage defects or in situations of more widespread cartilage loss, such as those that occur in osteoarthritis (OA) [24, 25].
Considering growth factors and their roles in signaling pathways, the progressive trend of each protein’s role determination in cartilage development, is remarkable. Fortier et al.  studied the role of growth factors in cartilage repair. They gathered all the known proteins in their study that were involved in this process. Mueller et al.  studied the regulatory mechanisms for cartilage and tendon cell phenotypes. In their study, known master regulators are predicted to be associated with the observed phenotypes, including TGF-β in monolayer cultures and PDGF BB in 3D cultures.
Considering the independent up-ward trend of tissue engineering, and systems biology, a remarkable synergy could be available in consonance with computational science (Fig. 1). Drawing a network of relationships among potential growth factors to select them accurately could be valuable in this order. Based on published works, it can be concluded that there is no comprehensive systems biology study on the cartilage growth factors that can draw up the existing relationship between them. Besides, to the best of our knowledge, there is no in-silico study of cartilage tissue engineering. In fact, in cartilage formation, several proteins are used therapeutically . However, there are so few resources that could demonstrate the most impressive of them to accelerate chondrocyte growth. Also, there is no available information about which protein plays a more significant role in the regulation of cartilage development.
[Insert Fig. 1]
Although accumulating the best growth factors based on the previous experiments and the existing data is accessible via in-vitro and in-vivo studies, there are many reports about the effects of using each growth factor without any coherence and correlation.
If there are some interactions between growth factors, the main issue is to find them out. Hence, in this work, we aim to define a network for considering the relation among cartilage growth factors.