**3. Tissue regeneration**

is not connected covalently to some core proteins. Proteoglycans are composed of GAG chains that are covalently linked to the core protein and considered to have a significant role in chemi-

body

**Cell Type Function Distribution Characteristics**

Throughout all loose and dense connective

Present in hyaline cartilage of articulations and fibrocartilage of intravertebral discs Found also in elastic

In blood vessels and skin throughout the

Flat, stellate cells with dark, ovoid, staining nuclei, and one or more

Microscopically may appear to be of different shapes because of the plane

Metabolically active with large vesicular nuclei and prominent

Cytoplasma pale and vacuolated because of high content of lipid and

presence of a large amount of rough endoplasmic reticulum that produce glycosaminoglycan and glycoprotein

Resemble fibroblast under light microscopy but ultrastructurally contain actin filaments for contraction

nucleoli

nucleoli

glycogen

In bone Basophilic cytoplasma resulting from

of sectioning

tissue

cartilage

Fibroblast Synthesize and secrete collagen,

molecules)

Chondroblast Synthesize and secrete

68 Tissue Regeneration

Osteoblast Synthesize and secrete

Myofibroblast Synthesize and secrete

Modified from Crammer and Bakkum [1].

**Table 1.** The cells of connective tissue.

matrix

elastic fibers, reticular fiber, and proteoglycan (among other

Support ligaments, tendons, bone, skin, blood vessels, and basement membranes

extracellular matrix of cartilage (collagen, elastic fiber and glycosaminoglycans) Support articular cartilage

extracellular matrix of bone

components of extracellular

Capable of contractility

Collagen is a major abundant fibrous protein in the extracellular matrix. Collagens, which constitute the primary structural element of the ECM, provide tensile strength, regulate cell adhesion, support chemotaxis and migration, and direct tissue development [4]. Recently, there have been already described 28 types of collagen. The main types of collagen found in

Collagen polypeptide chains are synthesized on membrane-bound ribosomes and fed into the lumen of the endoplasmic reticulum as large precursors, called the pro-α chains. Each pro-α chain then joins the other two to form a hydrogen-bond, triple-stranded hydrogen molecule known as a procollagen. After secretion, the fibrillar procollagen molecule divides to become

Fibronectin is an extracellular protein that makes cells adhere to the matrix. Fibronectin is considered as a large glycoprotein found in all vertebrates. Fibronectin usually exists as a

cal signaling among cells (**Figure 4**).

connective tissues are types I, II, III, V, and XI.

collagen molecules, which converge into fibrils [5].

**2.2. Collagen**

**2.3. Fibronectin**

Extracellular matrix is the primary factor required in the process of forming a new network and tissue. Along with the development found, many different factors can trigger the growth of ECM or used to create a synthetic ECM. Currently, ECM is involved in various mechanisms such as wound healing with or without the involvement of mesenchymal conditioned medium and neuronal regeneration capability associated with pathologic and/or neurodegenerative disease.

The process of wound healing is strongly influenced by the role of migration and proliferation of fibroblasts in the injury site. Indeed fibroblast is one part of ECM. The proliferation of fibroblasts determines the outcome of wound healing. Fibroblasts will produce collagen that will link to the wound, and fibroblasts will also affect the process of reepithelialization that will close the wound. Fibroblasts will produce type III collagen during proliferation and facilitate wound closure. During proliferation stage, fibroblasts proliferation activity is higher due to the presence of TGFstimulated fibroblasts to secrete bFGF. The higher number of fibroblasts also induces increasing of collagen synthesis. Collagen fiber is the major protein secreted by fibroblast, composed of extracellular matrix to replace wound tissue strength and function. Collagen fibers deposition was significant on 8–10 days after injury. The number of fibroblasts increases significantly, in correlation with the presence of an abundance of bFGF on 8–10 days after wounding.

Mesenchymal stem cell conditioned medium (MSCM) can be defined as secreted factor that referred to as secretome, microvesicle, or exosome without the stem cells which may found in the medium where the stem cells are growing. The use of MSCM as cell-free therapy has more significant advantages in comparison to the use of stem cells, mainly to avoid the need of HLA matching between donor and recipient as a consequence to decrease the chance of transplant rejection. Additionally, MSCM is more easy to produce and save in large quantity. The presence of human umbilical mesenchymal conditioned medium (HU-MSCM), will accelerate curing of the acute and chronic incision and/or burn wound by increasing the number of myofibroblasts and encouraging the expression of VEGF, TGF, bFGF, and also PDGF to promote wound closure.

improvement in proliferation, migration, and differentiation [13–15]. This evidence gives a new chance in the involvement of HU-MSCM to promote and recover from neuronal injury. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting that eliminates the antigens responsible for allograft rejection and maintains most of the ECM components, which can effectively guide and enhance nerve regeneration. In the field of tissue engineering by an in vivo model, a lot of successful carriers and matrices have been employed as a scaffold to promote direct

**Figure 5.** Microscopic anatomy of the extracellular matrix within the central nervous system (CNS). The three major compartments of the extracellular matrix in the CNS are the basement membrane, perineuronal net, and neuronal interstitial matrix. The basement membrane is found surrounding cerebral blood vessels, the perineuronal net is a dense matrix immediately surrounding neuronal cell bodies and dendrites, and the neuronal interstitial matrix occupies the

The Role of Extracellular Matrix in Tissue Regeneration http://dx.doi.org/10.5772/intechopen.75728 71

In conclusion, the extracellular matrix is the primary factor required in the process of forming a new network and tissue. Along with the development found, many different factors that can trigger the growth of ECM are used to create a synthetic ECM. Recently, ECM is involved in various mechanisms such as wound healing with or without the involvement of mesenchymal conditioned medium and neuronal regeneration capability associated with pathologic and or neurodegenerative disease. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting to eliminate the antigens responsible for allograft rejection and maintain most of the ECM components, which can effectively guide and enhance nerve regeneration. In the field of tissue engineering by an in vivo model, significant progress on matrices development have been utilized as a scaffold

axonal growth on peripheral nerve injury [16].

space between neurons and glial cells. Adapted from Lau et al. [7].

to promote direct axonal growth on peripheral nerve injury.

The authors declare there is no conflict of interest.

**Conflict of interest**

Recently, it has been mentioned that widespread neuronal cell death in the neocortex and hippocampus is an ineluctable concomitant of brain aging caused by diseases and injuries. However, recent studies suggest that neuron death also occurs in functional aging and it seems in related to an impairment of neocortical and hippocampal functions during aging processes. Data from WHO and Alzheimer report show increasing number of people suffering from dementia along with aging. Profoundly understanding the role of extracellular matrix (ECM) in influencing neurogenesis has presented novel strategies for tissue regeneration (**Figure 5**).

Central nervous system injury because of stroke vascular and amyloid plaque accumulation as the effect of Alzheimer's diseases may cause the disturbance astrocytes, fibroblasts, and oligodendrocyte precursors cell proliferation which may form a glial scar [8, 9]. Within this glial scar, upregulated proteoglycans like CSPGs and changes in sulfation patterns within the ECM result in the building of regeneration inhibition [10].

To solve the problem, some manipulation on the intrinsic extracellular matrix by using traditional herb such as *Ocimum sanctum* extract was already done. In the in vivo and in vitro model using human brain microvascular endothelial cells (HBMECs) which mimics bloodbrain barrier, the treatment of the extract may promote the cell proliferation on the hippocampus area and HBMECs in the condition upregulation of choline acetyltransferase (ChAT) enzyme [11, 12]. In addition, there is also a chance to use nanometer-sized scaffolds in the presence of other substrates such as vascular endothelial growth factor or hyaluronic acid with laminin. This scaffold may conduct a way to the regenerative capacity and functional recovery of the CNS to reconstruct formed cavities and reconnect neuronal processes. Thus, the artificial scaffold functions to enhance the communication between cells, allowing for

**Figure 5.** Microscopic anatomy of the extracellular matrix within the central nervous system (CNS). The three major compartments of the extracellular matrix in the CNS are the basement membrane, perineuronal net, and neuronal interstitial matrix. The basement membrane is found surrounding cerebral blood vessels, the perineuronal net is a dense matrix immediately surrounding neuronal cell bodies and dendrites, and the neuronal interstitial matrix occupies the space between neurons and glial cells. Adapted from Lau et al. [7].

improvement in proliferation, migration, and differentiation [13–15]. This evidence gives a new chance in the involvement of HU-MSCM to promote and recover from neuronal injury.

In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting that eliminates the antigens responsible for allograft rejection and maintains most of the ECM components, which can effectively guide and enhance nerve regeneration. In the field of tissue engineering by an in vivo model, a lot of successful carriers and matrices have been employed as a scaffold to promote direct axonal growth on peripheral nerve injury [16].

In conclusion, the extracellular matrix is the primary factor required in the process of forming a new network and tissue. Along with the development found, many different factors that can trigger the growth of ECM are used to create a synthetic ECM. Recently, ECM is involved in various mechanisms such as wound healing with or without the involvement of mesenchymal conditioned medium and neuronal regeneration capability associated with pathologic and or neurodegenerative disease. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting to eliminate the antigens responsible for allograft rejection and maintain most of the ECM components, which can effectively guide and enhance nerve regeneration. In the field of tissue engineering by an in vivo model, significant progress on matrices development have been utilized as a scaffold to promote direct axonal growth on peripheral nerve injury.
