Table 1.

Comparative constituents of natural BM and synthetic scaffolds to reconstruct and replicate the BM microenvironment for transplantation and regeneration.

BM Components, Architecture and Environmental Niches	BM and HC Components Functions	Scaffolds Components Mimicking the BM and HC Microenvironment	Comments	References
1. Bone Bones comprise mainly collagen type I and hydroxyapatite (HA).	Creating synthetic BM and HCs niches to mimic the natural BM and HCs environments using the structural components.	Bones support the body and hold the soft organs. Marrow is a site of hematopoietic stem cells.	Convenient to fabricate artificial BM and cancer mimicking scaffolds for BM and HC studies.	[7,24,25,26]
1a. Mineral component of bone 1a. Calcium component Heterogeneous composite mineral, 70% by weight of bone is a modified form of HA.	HA synthesized wet by direct precipitation of calcium and phosphate ions, and used up to 40% of HA in the scaffold fabrication. PLGA and PCL are ECM like polymers that render mechanical strength.	The hardness and rigidity of bone are due to the crystalline complex of calcium and phosphate, known as hydroxyapatite (HA).	Required amounts can be incorporated to build up structure.	[27,28]
1b. Trace elements Zinc, Silicon, Copper, Fluorine, Manganese, Magnesium, Iron, Boron and others elements are present.	Incorporating these trace elements into tissue engineered bone (TEB) scaffold at the time of fabrication. Doping the scaffolds with silicon, carbonate, and zinc simulate the natural bone environment.	Zinc contributes to tissue remodeling, protein and nucleic acid synthesis, cell proliferation, and remodeling ECM. Silicon is essential for bone, cartilage, organ, and connective tissues. Other elements such as copper, fluorine, manganese, magnesium, iron, and boron influence bone function.	Trace elements needed for the healthy functioning of bone cell viability and survival.	[29,30,31]
1c. Porous architecture Spongy and porous nature of the bone.	Desired pore sizes and pore microarchitecture can be created using appropriate size porogens at the time of scaffold fabrication.	Cell distribution interconnection, diffusion of nutrients and oxygen, especially in the absence of a functional vascular system.	Permeability as a function of porosity. Controlled porosity can be created in the 3-D scaffolds.	[32]
2.Extracellular matrix Collagen constitutes 90% of the matrix proteins, and accounts for 25 to 30% of the dry weight of bone Collagen type 1 is the predominant fraction of collagen, together with other proteins and mucopolysaccharides.	Synthesis of ECM like matrix Collagen type I and other mucopolysaccharides can be added to TEB scaffold at the time of synthesis Chitosan (CS) is another ECM-like material. It is a nontoxic, biocompatible, biodegradable cationic polysaccharide. It can be incorporated to TEB scaffold. Incorporating native or synthetic ECM into 3-D scaffolds.	Collagen with its triple helix tertiary structure and high mineralization imparts high tensile strength and high flexibility to bone. It is essential for tissue morphological organization and physiological function. Chitosan simulates the marrow environment. It also promotes electrostatic interactions with anionic glycos- aminoglycans (GAG) and proteoglycans. Incorporating native or synthetic ECM into 3-D scaffolds.	An important structural protein Chitosan is a natural biopolymer. It is easily available and widely used in tissue engineering. Direct transfer of native physio- logical and biochemical cues.	[33,34,35,36,37]
3. BM cells Osteoblasts, bone lining cells (BLC), osteocytes, osteoclasts, MSC, CAR cells, adipocytes, macrophages, and other cell types.	BM cells are in dynamic state of interactions with various cell types in BM environment. Studying the interactions of these different cell types help in understanding the mechanisms of their influence on HSC behavior. Varying combinations of these bone marrow cells in co-culture systems can be used for culturing in BM TE scaffold.	Osteoblasts involved in mineralization of bone and matrix proteins. Play a role in calcium homeostasis and bone resorption. Bone lining cells (BLC) function as a barrier for certain ions and induced osteogenic cells.	BM cellular functional interactions. HSC maintenance.	[16,38,39]
4. Interaction of BM cellular components	Co-cultures in 3-D with MSC increased proliferation and maintained HSC.	To maintain the microenvironment of hematopoietic stem and progenitor cell function.	Simulate the in vivo condition in vitro cultures.	[40,41]
5.Blood vessels-forming cells Interactions of multiple cell types in BM to form blood vessels.	HUVEC and MSC in perivascular niches self-assemble and form organized structures.	Blood vessel formation provides niches for hematopoietic stem cells that reside within the BM.	Vascularization facilitates the proliferation and maintenance of HSC.	[42,43,44,45]
6. Macrophages Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease	Co-culture of human induced (hiPSC)—mesenchymal stem cells and macrophages recapitulate the tissue remodeling process of bone formation.	Macrophages help to retain the HC niche Through various cellular and molecular mechanisms.	HSC maintenance is performed by BM macrophages by mobilizing depleted HSC.	[16,17,46,47]
7.BM Sympathetic nerves They involve in BM hematopoietic homeostasis by regulating HSC maintenance genes expression. Schwann cells localize close to HSCs and maintain HSC quiescence. Chemotherapy-induced bone marrow nerve injury.	Scope for studying co-cultures of neuronal cells with HSC supporting cells. Scope for creation of nerve tissue in BM environment.	Hematopoietic stem cell hibernation in the BM niche. Involve in BM function. Adult BM cells are sources of Schwann cells	Maintain HSC quiescence Repair of impaired hematopoietic regeneration.	[48,49]
8 Bone marrow fat The intimate relationship among adipocytes, osteoblasts, and hematopoietic stem. Lipid rafts, the glycoprotein microdomains.	Fat components can be incorporated to the scaffolds at the time of fabrication for creating BM environment in co-culture systems.	Fat primes homing-related response of HSC/PHSC to SDF-1, through CXCR4. Fat also binds bone with calcium and forms bone grease. Play a role in signaling process, enhance the responsiveness of HSPC to homing.	The association between bone, fat, hematopoietic stem cell numbers, cytokine levels, and aging has been demonstrated.	[18,19,50,51]
9. HSC cellular stress Oxidative stress and hypoxia.	Study of these conditions and induced effects of radiation and cytotoxic chemotherapy in 3-D scaffold.	Understanding the damage caused by external agents to the biology of HSC.	In vitro model of HSC cellular Stress.	[52]
10. BM niche model of tissue and fluids.	Engineered bone marrow (eBM) on ‘bone marrow-on-a-chip’ microfluidic device is extended 3-D culture model.	Long term cultures of Bone HSC and PHSC. Myeloid toxicity studies.	Advanced stem Cell therapeutics.	[53,54,55]
11. Hematopoietic malignancies CLL, ALL, CML, AML, MML leukemia and multiple myeloma	Fabrication of BM and HC environments mimicking 3-D scaffolds.	BM and cancer in vitro drug testing models.	In vitro disease model.	[56,57,58,59]

As shown in Table 2, biomimetic 3-D scaffolds are fabricated for creating a microenvironment of various cellular components, including the ECM and vascular systems, with the required physical characters of native tissue.