Progress in Biomaterials

https://doi.org/10.1007/s40204-019-00125-z

REVIEW PAPER

Bone tissue regeneration: biology, strategies and interface studies

Mojtaba Ansari1

Received: 2 August 2019 / Accepted: 15 November 2019

© The Author(s) 2019

Abstract
Nowadays, bone diseases and defects as a result of trauma, cancers, infections and degenerative and inflammatory conditions
are increasing. Consequently, bone repair and replacement have been developed with improvement of orthopedic technolo-
gies and biomaterials of superior properties. This review paper is intended to sum up and discuss the most relevant studies
performed in the field of bone biology and bone regeneration approaches. Therefore, the bone tissue regeneration was inves-
tigated by synthetic substitutes, scaffolds incorporating active molecules, nanomedicine, cell-based products, biomimetic
fibrous and nonfibrous substitutes, biomaterial-based three-dimensional (3D) cell-printing substitutes, bioactive porous
polymer/inorganic composites, magnetic field and nano-scaffolds with stem cells and bone–biomaterials interface studies.

Keywords  Bone regeneration · Biology · Biomaterials · Biocompatibility · Tissue engineering

Introduction stem cells from encompassing tissues to differentiate to bone

cells” properties (Sheikh et al. 2019). Autografts, coupled
Bone presents numerous performs including principal back- with difficulties, come across post-surgery containing nerve
ing structure designed formation, the binding place for mus- injury, infections, morbidity and chronic pain at the donor or
cles, ligaments and tendons, mechanical support and shield acceptor site. Besides, allografts have the potential of dis-
of most important tissues (Pajarinen et al. 2019). Besides, ease conduction, infection and incite immune reactions fol-
hematopoiesis and vital mineral materials are provided by lowing the implant rejection. Investigators have attempted to
bone marrow structure (Ansari et al. 2011). Musculoskel- solve these complications of bone grafts by means of natural
etal diseases including rheumatoid arthritis, osteoarthritis, or synthetic biomaterials (Ansari and Eshghanmalek 2019).
osteoporosis, low back pain and limb trauma are all com- This study concentrates on bone biology, bone tissue
monly developing and painful (Roshanbinfar and Ansari regeneration strategies including synthetic substitutes alone,
2013). Most bone fractures occur as a result of inconven- scaffolds combined with active molecules, nanomedicine for
ient or incompetent bone regeneration (Naghib et al. 2012). healing of bone trauma and defects, cell-based combina-
Large segmental bone fractures did not repair instinctively tion products with cells from various sources, biomimetic
and require orthopedic operation. Furthermore, spinal fusion fibrous and nonfibrous substitutes, biomaterial-based three-
surgeries may result in non-union frequently (Eslami et al. dimensional (3D) cell-printing substitutes, bioactive porous
2018). Approximately bone defects are currently cured using polymer/inorganic composite and magnetic field and nano-
bone autograft (the gold standard for surgeons), allografts scaffolds with stem cells, bone biomaterial interface stud-
and biomaterial substitutes with biocompatible, osteointe- ies. The interactions between bone cells and biomaterials,
grative “intense communications among the host bone tissue as they play a crucial role in bone repair.
and the substituted materials”, osteoconductive “the ability
of materials to be colonized by host bone cells and blood
vessels” and osteoinductive “motivate host mesenchymal Bone biology

Bone structure
* Mojtaba Ansari
[email protected]; [email protected]
Bone is not homogeneously solid, but it is arranged of liv-
1
Department of Biomedical Engineering, Meybod University, ing bone cells set in a biomineral medium. Actually, bone is
Meybod, Iran

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 Progress in Biomaterials

designed by the toughening of this medium nearby entangled storage and role in acid–base balance). The four most impor-
cells. Bone itself involves chiefly of collagen fibers and an tant cells including: osteogenic, osteoblasts, osteocytes, and
inorganic bone mineral in the form of small crystals (Uskok- osteoclasts (together recognized as the basic multicellular
ovic et al. 2019). unit (BMU)) contained in bone regeneration and structure
are shown in Fig. 1 (Kular et al. 2012).
Bone cells and matrix Osteoblasts are derived from osteoprogenitor cells of
mesenchymal origin in bone marrow and other connective
The biomineral medium of bone contains about 30% organic tissues. They are differentiated and proliferated to osteo-
and 70% inorganic segments (Wang et al. 2019). Almost, blasts before bone formation, stimulated through bone mor-
90% of this organic segment is collagen, whereas the resid- phogenetic proteins (BMPs). These cells are responsible for
ual 10% was mostly non-collagenous proteins, lipids, proteo- growing or remodeling of bone (Standring 2016). Also, their
glycan molecules, osteopontin (OPN), and other bone matrix roles are the synthesis, deposition and mineralization of the
proteins (Hu et al. 2019). The bone matrix proteins play vital bone matrix by producing a protein mixture called osteoid.
role in mechanical strength and tissue adhesive character- Mature osteoblasts may convert to a layer of cuboidal cells,
istics. Principally, the mineral phase of bone is hexagonal that they can undergo apoptosis or become osteocytes and
hydroxyapatite (HA) crystal (Qiu et al. 2019). The chemical bone-lining cells (Sikavitsas et al. 2001).
formula of crystalline HA is ­Ca10(PO4)6(OH)2 (Türk et al. Osteocytes are the most abundant cell type in bone tis-
2019), where surface binding and electrostatic interactions sue (Noble and Reeve 2000). They are described by a star-
­ a2+ and (­ PO4)3− (Samavedi et al.
are related to presence of C shaped morphology. Osteocytes are derived from MSCs
2013). The HA crystals are organized parallel to the long that undergo osteoblastic differentiation. These are inactive
axes of collagen fibers by self-assembly of collagen triple osteoblasts that have become trapped in the bone that they
helices (Wang et al. 2012). have created. They maintain connections to other osteocytes
and osteoblasts. They are vital for communication within
Bone cells bone tissue. Furthermore, osteocytes have been presented
to react to several biochemical signaling paths and contrib-
Further to mineralized bone milieus, bone cells are addition- ute to regulation of calcium and phosphate homeostasis.
ally critical to the function of bones. Bone is responsible for Malfunction of the osteocyte cells growths leads to bone
several roles in the body containing mechanical functions brittleness and may result in osteoporosis (Standring 2016;
(protection, shape, movement and locomotion), synthetic Teti 2011).
functions (synthesis of blood cells) and metabolic functions Bone-lining cells are inactive osteoblasts that reside on
(mineral storage, regulation of calcium and phosphate, fat bony surfaces (Franz Odendaal et al. 2006). Lining cells play

Fig. 1  Four types of cells are

found within bone tissue includ-
ing osteogenic cells, osteocytes,
osteoclasts, and osteoblast
(Behzadi et al. 2017)

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Progress in Biomaterials

a significant role in coupling bone resorption to bone forma- hard callus), which is noticeable on X-rays some weeks
tion and in calcium hemostasis and in osteoclastic differen- after the fracture. Bone remodeling, the ultimate stage of
tiation. They also act as hurdle that avoids direct interface bone healing, continue more than a few months. In regen-
among osteoclasts and bone matrix (Luginbuehl et al. 2004). eration, bone regenerates to form and converts condensed,
Osteoclasts are large cells with more than one nucleus returning to its original form (Dimitriou et al. 2005). Fur-
that are differentiated from the hematopoietic lineage. Their thermore, blood circulation in the region progresses. Once
job is to break down bone (Boyle et al. 2003). They release suitable bone restorative has followed, weight bearing
enzymes and acids to dissolve minerals in bone and digest inspires bone healing. Briefly, the stages of bone fracture
them. This process is called resorption. Osteoclasts help repair are presented in Fig. 2.
remodel injured bones and create pathways for nerves and
blood vessels to travel through. Irregularities in osteoclastic
activity distinguish diseases such as osteoporosis (increased
osteoclast activity) and osteopetrosis (Kular et al. 2012; Bone regeneration strategies
Standring 2016).
At present, the “conventional standard” healing of patients
Mechanism of bone repair suffering from long or imperfect bone treatment is to
implement bone grafting, by means of either an autograft
Bone fracture regeneration is a multipart, arranged, or an allograft. Though, there are problems to bone graft-
reformative procedure that contains a vital numeral of ing. Subsequently, a more maintainable, long-term healing
progenitor cells along with inflammatory, endothelial and plan is necessary. To that end, bone graft replacements
hematopoietic cells. The bone restorative procedure has are being concocted to aid damaged fracture treatment.
three intersecting phases: inflammation, bone production Based on the gravity of the trauma, the main strategies are
and bone remodeling (Schindeler et al. 2008). Inflamma- established for bone repair:
tion begins instantly once the bone is broken and continues
for more than a few days. As soon as the bone is broken, 1. Synthetic substitutes alone
there is bleeding into the region, result in inflammation 2. Scaffolds combined with active molecules
and coagulation of blood at the breakage location (Sikavit- 3. Nanomedicine for healing of bone trauma and defects
sas et al. 2001). This is responsible for the primary funda- 4. Cell-based combination products with cells from various
mental strength and basis for new bone formation. Bone sources
production initiates once the coagulated blood formed by 5. Biomimetic fibrous and nonfibrous substitutes
inflammation is substituted with fibrous tissue and carti- 6. Biomaterial-based 3D cell-printing substitutes
lage (recognized as soft callus). As regeneration growths, 7. Bioactive porous polymer/inorganic composite
the soft callus is switched with hard bone (identified as 8. Magnetic field and nano-scaffolds with stem cells.

Fig. 2  Stages of bone fracture

repair and remodeling

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 Progress in Biomaterials

Suitable material selection of damaged bone et al. 2013; Diba et al. 2014; Dziadek et al. 2017). For exam-
substitute ple, nanostructured monticellite ­(CaMgSiO4) ceramic and
its composites (with HA) showed good in vitro bioactiv-
Demineralized bone matrix (DBM) was produced with ity, biocompatibility, and antibacterial properties for bone
osteoconductive and osteoinductive properties (Giannoudis tissue engineering application (Chen et al. 2008; Kalantari
et al. 2005). The preferred choice for DBM synthesis was et al. 2017; Kalantari et al. 2018a, b, c, 2019; Kalantari and
reported cortical bone as a result of osteoinductive with a Naghib 2019).
lesser antigenic possibility in comparison to cancellous bone
(Burg et al. 2000). Utilization of viscous spongy cellulose Scaffolds combined with active biomolecules
revealed that it was extremely suitable for bone regeneration.
The implanted cellulose in the femoral bone of rats showed The approaches can be categorized in three classifications:
that osteoconduction was mostly happened (Ekholm et al. (a) application of recombinant growth factors and a combi-
2005). Recently, bacteria strains secretion-derived bacterial nation of growth factors associated with a natural medium
cellulose was introduced as an emerging player in tissue or calcium phosphate substantial carrier, (b) application of
engineering because of its extremely good cytocompatibil- proteins to target cellular receptors, and (c) application of
ity and physiochemical properties. Therefore, its modified small molecules that target the signaling pathway (Ansari
compounds were used for bone regeneration (Stumpf et al. et al. 2018). Figure 3 presents the general schematic pres-
2018). Synthetic media have similarly been evaluated as entation of the scaffold loaded with active biomolecules for
acellular bone tissue engineering materials. Hence, poly- accelerate bone repair. The main growth factors have already
l-lactide (PLLA) films were used to repair 1-cm trauma been used in clinics included BMP-2, BMP-7, and rhPGDF-
in the radius bone of mature rabbits, and histologic results BB (Ho-Shui-Ling et al. 2018). The growth factors effect on
indicated that the cortical bone was redeveloped over the bone progenitors by interrelating with their particular recep-
defect (Zhang et al. 2006). Poly-ε-caprolactone-co-lactide tors, which activate the chemical signaling pathways result
was used as a different potential filler material in bone in bone development. Several studies have previously been
defect, and investigated in non-osseous usage. To evaluate done on BMP-2 associated with a type I collagen porous
the absorption and biocompatibility of this copolymer, it was structure as delivery service, for application in open tibial
used in femoral defect of rat (Helminen et al. 2002). Photo- fractures and in spinal defects (Bessa et al. 2008). In a study,
crosslinkable polyanhydrides constituents demonstrated the it is combined with a titanium or PEEK structure for appli-
convinced benefits for orthopedic regeneration. In this case, cation in anterior lumbar interbody fusion (Vaidya et al.
the photopolymerizable component enhanced microfabrica- 2008). It is well known that bone restoration in response
tion probability of porous scaffolds. Also, mechanical inves- to BMP-2 is dose dependent. High doses of BMP-2 may
tigations proved reliability of these polymers for tissue engi- result in osteolysis. So, the potent activating characteristic of
neering applications (Pakulska 2016). Calcium phosphate bone repair of BMP-2 needs to be further optimized (Bruder
and silicate-based bioceramics were prominently featured et al. 1994). Latest documents in a rat femoral bone fracture,
among used biomaterials for bone regeneration (Samavedi applied PLGA as a polymeric carrier as a nano reservoir for

Fig. 3  Schematic presentation of macro/micro/nano-porous scaffold loaded with active biomolecules for accelerate bone regeneration (Yi et al.
2016)

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Progress in Biomaterials

BMP-2 delivery (Zheng et al. 2010). The result revealed that a normal fibrin medium, incorporated with a mechanical
it is conceivable to adjust the dose of BMP-2 in vivo. This ceramic constituent (HAP/TCP granules), may be responsi-
controlled dose influenced the dimensions of bone forma- ble for structural stability and osteoconduction for the period
tion, and enhanced the kinetics of bone renovation by means of healing (Portale et al. 1984).
of delivery of BMP-2. Microorganism-derived polyhydroxyalkanoate (PHA)
BMP-7 growth factor is osteoinductive which is studied scaffolds have emerged as polymeric promising biomate-
for the clinical application (Bostrom and Seigerman 2005). rials with excellent potential for bone tissue engineering
Collagen type I incorporated with BMP-7 in the paste form applications because of their good biodegradability, biocom-
is used for recalcitrant long bone and spine surgical treat- patibility and vascularization, and unique physiochemical
ment. Investigations on a sheep model indicated that the properties. They induced cell adhesion and growth on their
BMP-7 paste may be able to incorporate with a porous scaf- porous structure for bone regeneration (Lim et al. 2017).
fold to initiate long bones regeneration (Haidar et al. 2009). Lalzawmliana et al. (2019) reported that mesoporous bioac-
rhPDGF-BB in form of device/drug product was employed tive glass (MGB) scaffolds as third-generation biomaterials
for hindfoot and ankle fusion (Solchaga et al. 2012). PDGF, were used for regeneration of critical bone defects, and MGB
by functioning on PDGF receptors, motivates the employ- scaffolds should have large interconnected pores for improv-
ment, migration and proliferation of cells containing mes- ing growth, adhesion and proliferation of osteoblast cells and
enchymal stem cells and stimulates the neovascularization assisting in angiogenesis. In recent studies, effect of three-
by growing vascular endothelial cells at the location of bone dimensional (3D) scaffolds and their fibrous order on bio-
repair. compatibility were investigated. The results showed that 3D
Presently, a β-TCP/PDGF scaffold was employed to aligned nanofibrous scaffolds provided cell behaviors better
provide osteoconductivity for bone repair. In a study on than two-dimensional (2D) scaffolds, because of their more
patients devoted to hindfoot or ankle arthrodesis, healed with accommodation for the attached cells, and loading more bio-
rhPDGF-BB/β-TCP, gave rise to comparable fusion extents, active molecules for promotion of cell growth, proliferation,
minus pain, and less side effects in comparison to healing migration and differentiation. Nevertheless, a big challenge
with autograft (Bateman et al. 2005). was mentioned for them that related to their static status.
Other growth factors like GDF-5 are kind of BMP group For example, they cannot remodel their stiffness, surface
that encourages bone formation (Nickel et al. 2005). Sev- chemistry and roughness in an in situ and dynamic situa-
eral researches have confirmed rhGDF-5 has the potential of tion, so cannot mimic the function of main tissue (Jin et al.
bone induction tissue growth. A bone substitute rhGDF-5/ 2018). Rather et al. reviewed the dual functional strategies
(β-TCP) was applied for dental implants and medical cure to spread osteogenesis coupled angiogenesis through differ-
of periodontal syndrome. The in vitro results indicating that ent scaffolds. Vascularization played the important role to
rhGDF-5 has the potential to promote gene expression and carry oxygen, nutrients and essential molecules and growth
production of the ECM proteins such as collagen type II and factors into damaged tissue. Then, the angiogenesis and
aggrecan (Poehling et al. 2006). osteogenesis communicated harmoniously together for bone
Peptides, they have the ability to access cellular receptors, regeneration, because many studies confirmed the crosstalk
are substitutes for recombinant growth factors which are able between bone progenitor cells and endothelial cells. There-
to produce easily. Bioactive B2A (B2A2-K-NS) synthetic fore, the scaffolds containing osteoinductive and angioinduc-
polypeptide applied to augment spinal fusion (Omrani et al. tive factors released various types of molecules to stimulate
2016). HAP/β-TCP incorporated with B2A granules were osteogenesis and angiogenesis (Rather et al. 2019). The
investigated for foot and ankle fusion. studies showed that many scaffolds were investigated in
In vitro results indicate that B2A induces chondrogenic the field of bone repair with the purpose of bettering cell
differentiation and improves the in vivo healing of injured growth, adhesion and proliferation, osteogenic differentia-
cartilage in an osteoarthritis model (Ho-Shui-Ling et al. tion, vascularization, and mechanical properties, but Roseti
2018). Collagen is a major protein of the ECM and contrib- et al. (2017) reported that the further depth studies will be
utes in osteoblast attachment and activity (Ansari and Moz- needed for using the bone tissue engineering scaffolds in
tarzadeh 2012). P-15 is a 15 amino-acid protein obtained clinical application.
from collagen and promotes the differentiation of mesen-
chymal stem cells. P-15 has been applied in combination Nanomedicine for healing of bone trauma
with bone inorganic for spinal fusion, non-union fractures and defects
and joint reconstruction with acceptable results (Bhatnagar
et al. 1999). Besides, small molecules applied as controllers One of the most important drawbacks in the healing of open
of bone bulk. Parathyroid hormone has a vital character in fractures is infection. The failure of the tissue obstruction
controlling calcium phosphate digestion. PTH entrapped in among the rupture location and the external milieu result

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 Progress in Biomaterials

in bone bacteriological infection and contamination (Broos (ROS) and destroy their contamination hazard as it is shown
and Sermon 2004). in Fig. 4 (Long et al. 2006).
Besides, it was proved that Staphylococcus aureus (is a One of the most frequently used NPs for diminution of
Gram-positive, round-shaped bacterium that is a member infection risk in orthopedic distress is silver (Ag) NPs. Their
of the firmicutes, and it is a usual member of the micro- extensive antibacterial performance is proved. They are
biota of the body) may attack intracellular sites contained extensively applied to remove various bacteria containing
by osteoblasts, result in complications in microbial eradi- S. aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseu-
cation and amplified vulnerability to osteomyelitis subse- domonas aeruginosa, and Escherichia coli.
quent contamination (Join Lambert et al. 2005). The infected Polymethylmethacrylate (PMMA)-based bone cement,
fractures need management including medical debridement, consisting of Ag NPs (about 50 nm), completely prevented
antibiotics, and skeletal stabilization. Frequently, antibi- the propagation of Staphylococcus epidermidis, methicillin-
otic-contained cement made of polymethylmethacrylate resistant S. epidermidis (MRSE), and methicillin-resistant
(PMMA) is implanted to harmonize the antibacterial activ- S. aureus (MRSA), while PMMA bone cement contained
ity (Schade and Roukis 2010). The growth and differentia- 2% of gentamicin sulfate avoided only the propagation of
tion of osteoblasts and osteoclasts are controlled by growth S. epidermidis (Abid et al. 2017). In additional research, an
factors, cytokines produced in the bone-marrow ECM, and antibacterial HA NPs scaffold was created, and antibacterial
adhesion structures that facilitate cell–cell and cell–ECM properties were attained by the addition of Ag NPs.
communications (Lu et al. 2012). In another study, selenium (Se) NPs were employed to
Numerous categories of antibacterial nanoparticles (NPs) coat a bioactive glass-based structure (­ SiO2 and molar ratio
and nano-sized carriers for antibiotic delivery have been of P to Ca = 1/5) fabricated by the foam replica technique.
confirmed to be applicable in curing infectious diseases, The results indicated that this scaffold has antibacterial
containing antibiotic-resistant ones, in vitro and in vivo. activity (Fathi-Achachelouei et al. 2019)..
For instance, several NPs are able to join to the membrane
of microorganisms by electrostatic interface and destruct Cell‑based combination products with cells
the unity of the microorganism membrane (Banerjee et al. from various sources
2011). Another mechanism is that designed NPs are able to
produce massive oxidative stress to microorganisms through Tissue-particular cells such as osteoblasts maybe employed
free radical construction such as reactive oxygen species as the cellular constituent of bone transplants. Several kinds

Fig. 4  Toxicity mechanisms
of NPs and their ions (e.g.,
silver and zinc) against bacteria
by induce oxidative stress by
means of the production of
reactive oxygen species (ROS).
The ROS is able to conclusively
break bacteria (e.g., their mem-
brane, DNA, and mitochondria)
culminating in bacterial death
(Hajipour et al. 2012)

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Progress in Biomaterials

of stem cells have been mostly used through the construc- Pluripotent human embryonic stem cells (hESCs) are
tion of bone grafts (Omrani et al. 2019). Multipotent adult obtained from human blastocysts. Effective differentiation
mesenchymal stem cells (MSCs) show unlimited differen- of hESCs into the osteogenic lineage has been confirmed
tiation capacity into various kinds of cell lineages, contain- in frequent reports mutually in vitro and in vivo. Actually,
ing osteoblasts and chondrocytes (Baksh et al. 2004). Adult following osteogenic stimulation, hESCs demonstrated to
MSCs perform as an inducible backup potency for tissue retain molecular and fundamental characteristics similar to
restoration following damage, and have been considered bone cells by means of the creation of mineralized bone
broadly for bone fracture regeneration. MSCs obtained from in vitro. Osteogenic cells derived from ESCs seeded on
numerous diverse sources containing bone marrow, synovial poly(d,l-lactic-co-glycolic acid)/HA scaffold showed sub-
membrane, skeletal muscle, and adipose tissue. Cell-based stantial in vivo bone construction in immunodeficient mice
therapy with allogenic BMSCs implants is operative in bone through subcutaneously seeding (Tang et al. 2012).
regeneration in different animal bone defect models. In ini- Induced pluripotent stem cells (iPSCs) have been origi-
tial clinical studies, autologous BMSCs have been cultured nated from adult somatic cells such as skin fibroblast (Kim
on bio-ceramic scaffold to heal big bone defects. Local trans- et al. 2010). IPSCs have the capacity to differentiate to all
plantation at the defect situate of MSCs led to widespread cell types. IPSCs obtained from embryonic source have the
fusion at 5–7 months after surgery (Cancedda et al. 2003). ability to produce MSC-like cells in vitro which presented
Another study indicated bone repair in rabbit skull defects the capability of more differentiating property to osteoblast
healed with autologous, osteogenically induced adipose- cells, whereas similarly indicating osteogenic capacity
derived stem cells (ADSCs) transplanted onto fibronec- comparable to that of BMSCs in vivo. Furthermore, in vivo
tin-coated polylactic acid scaffold (Di Bella et al. 2008). investigations have confirmed that MSC-like cells obtained
Additional study showed cranial bone defect regeneration from iPSCs present the capability to develop mature min-
in canine by means of osteogenically induced ADSCs trans- eralized construction similar to bone structure (Wu et al.
planted onto a coral structure (Aimaiti et al. 2011). In a dif- 2017).
ferent research, calvarial defects treated through autologous Endochondral bone tissue engineering using progenitor
ADSCs/fibrin glue/autologous cancellous bone graft. After cells such as chondroprogenitors has been lately demon-
2 months, new bone mineralization and complete calvarial strated. Several researches presented that articular chondro-
integrity were observed (Lendeckel et al. 2004). cytes are able to be stimulated to endochondral ossification
Multipotential synovial membrane-derived MSCs and generate TGFβ-1 and BMP-2 (Perez et al. 2018). In a
(SMSCs) stromal cells can operate as a healing substitute study, chondrocyte cell seeded on BMP-2-loaded polycap-
for focal cartilage damages and have capability to differ- rolactone (PCL) scaffold which subcutaneously implanted
entiate to osteogenesis. Stimulatingly in a current research, in vivo result in bone formation (Lee and Shin 2007).
SMSCs from knee joints presented greater osteogenic and
adipogenic potential than SMSCs of hip joints (Kristjánsson Biomimetic fibrous and nonfibrous substitutes
et al. 2013).
Dental pulp-derived stem cells (DPSCs) have lately being Bone tissue has a mineralized construction. Biomimetic
discovered for bone tissue engineering. DPSCs present the composite substitute with a mineral constituent were used
low percentages of morbidity, widespread differentiation broadly for bone repair. The mineral component induces
capacity into chondrogenic, and osteogenic cell lines, and structural integrity and osteoconductive properties to the
expression of bone markers in vitro and in vivo (d’Aquino scaffold. HA is frequently used for the reason that has the
et al. 2008). Alginate microsphere DPSCs carrier has the potential to simulate the natural minerals part of bone.
osteogenic potential through detecting improved mineraliza- Besides, other calcium phosphate or bioglass were simi-
tion and upregulated intensities of osteogenic genes (Mosha- larly used for their biocompatibility. Using dioxane/water
verinia et al. 2012). DPSCs seeded/collagen-HA-poly(l- as a solvent, nano-HA/PLLA nanofibers composite scaf-
lactide-co-ɛ-caprolactone) scaffold confirmed effective ECM folds through TIPS (thermally induced phase separation)
mineralization of osteoblast (Akkouch et al. 2014). Some technique were fabricated. The high surface area of the
tissues for instance placenta, umbilical cord blood (UCB) nanofibrous permits further the HA to be exposed, which
and umbilical cord tissue are different sources of MSCs is appropriate for bone tissue regeneration (He et al. 2009).
(Jin et al. 2013). The regenerative capability of RGD-func- In another study, HA was incorporated into electrospun
tionalized microporous calcium phosphate cements (CPC) nanofibers, then utilized a gelatin-apatite precipitate homog-
contained UC MSCs and BM MSCs were compared in a rat enized in an organic solvent with polylactide-co-caprolac-
bone defect model. The results showed comparable great tone (PLCL). For the duration of the precipitation reaction,
bone inorganic compactness, new bone formation and vas- the Ca/P proportion was reserved to 1.67 to guarantee stoi-
cularization in vitro and in vivo (Gan et al. 2018). chiometric apatite fabrication. Just the lowest concentration

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 Progress in Biomaterials

of gelatin-apatite leads to a growth in normal strength (Kim Bioactive porous polymer/inorganic composites
et al. 2006).
Lately, electrodeposition method has been developed that The artificial and biodegradable, polymer/inorganic bioac-
decreases the mineralization time. To demonstrate the flex- tive part compounds are used as bone tissue engineering
ibility of the technique, electrodeposition has been effec- supports as a result of their formability, bioactive perfor-
tively made on both electrospun PLLA fibers and phase- mance and regulating biodegradation kinetics (Rezwan
separated PLLA fibers. Consequently, electrodeposition et al. 2006).
confirmed to be a fast and operative method to mineralize Two categories of biodegradable biopolymers are pre-
a bone tissue scaffold (Wei and Ma 2006). Collagen, in the sented: the natural polymers containing polysaccharides
form of injectable hydrogels, membranes, or sponges, exten- such as starch, alginate, chitin/chitosan, hyaluronic acid,
sively employed for bone tissue regeneration. Individually, proteins for instance collagen, fibrin gels, silk and, as rein-
as composite with calcium phosphate structures such as HA; forcement, a diversity of bio-fibers including lignocellu-
Several instances include, collagen/HA/chitosan or collagen/ losic natural fibers, and the synthetic polymers are used
HA/alginate hydrogels (Teng et al. 2008). as 3D scaffolds in bone tissue engineering, are saturated
poly-α-hydroxy esters, containing polylactic acid (PLA)
Biomaterial‑based 3D cell‑printing substitutes and poly glycolic acid (PGA), as well as polylactic-co-
glycolide (PLGA) copolymers (Gentile et al. 2014).
3D printing employs 3D images of the bone trauma anat- PPF (polypropylene fumarate) has been used as an
omy, usually acquired from computed tomography (CT) injectable bone substitute scaffold for conducted tissue
scans, using a calculating software, to fabricate a bone graft regeneration. It was similarly utilized as a substrate for
substitutes (BGS) structure that matches to a bony defect osteoblast cultures. The growth of composite substrates
(Burleson and DiPaola 2019). The personalized bone graft adjoining polypropylene fumarate and mineral elements,
substitute form is fabricated using a 3D printer to control the such as HA or bioglasses, in contrast with the broad inves-
BGS mechanical features and substantial parameters. The tigation works devoted to PLGA and PLA composites
composition optimization confirms an improved correspond- (Chen et al. 2012).
ence among the BGS and the patient’s anatomy, permitting Aliphatic polyesters PHAs manufactured through bac-
the regeneration. Metallic replacements manufactured by teria under unstable progress situations. They are com-
titanium are the further most extensively used. Titanium monly biodegradable (through hydrolysis), biocompatible
plates are usually employed to immobilize bone parts in and thermoprocessable (Lizarraga-Valderrama et al. 2016).
jaw operations. 3D printing is similarly being studied for These fascinating properties make them suitable for bio-
orthopedic purposes: for acetabular ruptures, ankle defects medical applications in particular tissue engineering. PHA,
and further bone defects due to bone fracture, spurt fissure principally poly-3-hydroxybutyrate (PHB), copolymers of
of spine, bone cancer and orbital ground repair. The tailored 3-hydroxybutyrate and 3 hydroxyvalerate (PHBV), poly-
spongy implant printed using T ­ i6Al4V presented outstanding 4-hydroxybutyrate (P4HB), copolymers of 3-hydroxybu-
physicochemical features and biological function such as tyrate and 3-hydroxyhexanoate (PHBHHx) and poly-3-hy-
biocompatibility, osteogenic property, and bone regeneration droxyoctanoate (PHO) were confirmed to be appropriate for
(Alvarez and Nakajima 2009). Bioceramics and biopolymers bone tissue regeneration (Ke et al. 2017).
such as polyetheretherketone (PEEK) are currently custom Degradation products of bioglasses, especially the 45S5
designed, and are presently being investigated at the pre- Bioglass structure, regulate the gene activation that manages
clinical phase (Yan et al. 2015). PCL/HA composite is being osteogenesis and the fabrication of growth factors (Xynos
studied for the repair of gingival recession concomitant with et al. 2001). HA and silicon have a vital character in the
bone and gingival tissue repair (Osathanon et al. 2017). bone mineralization and gene expression, which requires
In a recent study, a mandible bone was repaired via greater than before attention in the substitution of silicon
human amniotic fluid-derived stem cell (hAFSC)-laden for calcium into HA structure (Arvidson et al. 2011). In vivo
hydrogel, a mixture of PCL and tricalcium phosphate (TCP), results have revealed that bone remineralization into silicon-
and pluronic F127 (Fig. 5b). The PCL/TCP and hAFSCs doped HA particles has been significant larger than that pure
mixed with the combination of hydrogel were reproduced in HA. Bioactive glasses lately have been used as scaffold,
a type I design with a Pluronic F127 impermanent support filler or coatings of polymers and, as porous constituents,
(Fig. 5c). Subsequently induction of osteogenic differentia- which contains melt-derived and sol–gel-derived bioglasses
tion for 28 days (Fig. 5d), they stained the constructions with (Wang and Yeung 2017).
Alizarin Red S; staining at the surface of the 3D bone con- In vivo and in vitro evaluation of crystalline or amor-
structions showed calcium deposition in the hAFSC laden phous calcium phosphates, in bulk, coating, powder, or
hydrogel (Fig. 5e). porous form, induce the attachment, differentiation, and

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Progress in Biomaterials

Fig. 5  Mandible bone regeneration. a 3D CAD model identified 3D-printed mandible bone defect construct, which was cultured in
a mandible bony defect from human CT image data. b Visualized osteogenic medium for 28 days. e Osteogenic differentiation of hAF-
motion program was generated to construct a 3D architecture of SCs in the printed construct was confirmed by Alizarin Red S stain-
the mandible bone defect using CAM software. c 3D printing pro- ing, indicating calcium deposition (Jang et al. 2018)
cess using integrated organ printing system. d Photograph of the

proliferation of osteoblasts and mesenchymal stem cells with growth factors and signaling factor, magnetically aided
(Rezwan et al. 2006). freezing and defrosting of stem cells, magnetically aided
scaffold and coating constructions are able to improve bone
Magnetic field and nano‑scaffolds with stem cells restoration. Animal research presented that SMFs with mod-
erate intensity improved the bone mineral compactness and
Innovative approaches are using magnetic nanoparticles bone repair (Fitzsimmons et al. 1995).
(MNPs) and magnetic fields to improve bone repair effi- SMFs may possibly modify cell functions such as the
ciency containing osteogenic improvements by means of attachment, morphology, proliferation, differentiation, apop-
magnetic fields, MNPs and magnetic approaches to develop tosis, gene expression, in particular osteogenic differentia-
the cells, scaffolds and growth factor conveyances including tion for different kinds of cells, containing BMSCs, human
cell tagging, targeting, designing, and gene modifications osteosarcoma cell lines MG63, human adipose-derived
(Panseri et al. 2012). The process of scaffolds containing MSCs, and dental pulp stem cells (DPSCs) due to electro-
MNPs using magnetic fields and stem cells to improve bone dynamic interactions and magneto mechanical interactions
redevelopment were recognized as including the motiva- (Xia et al. 2018b). Superparamagnetic iron oxide nanopar-
tion of signaling trails containing MAPK, integrin, BMP ticles (SPIONs) are encouraging for targeted drug delivery,
and NF-κB (Gonçalves et al. 2016). Static magnetic fields tissue engineering, hyperthermia, gene therapy, imaging and
(SMFs), pulsed electromagnetic fields (PEMFs), rotating cell tracking purposes. SPIONs without a magnetic field can
magnetic fields (RMFs) and alternating electromagnetic improve the tissue repair productivity, be responsible for
fields have the potential to improve the defect healing, dynamic mechanical motivations for bone regeneration,
bone mineral density, attachment of implants among bone encourage osteogenic differentiation of BMSCs, and develop
tissue (Xia et al. 2018b). Combination of magnetic fields bone healing in vivo (Santhosh and Ulrih 2013).

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 Progress in Biomaterials

In a study, gelatin/SPION-scaffold were implanted in non-magnetized control. SPIONs/nHA and PLA nanofibrous
the incisor sockets of rat model which improved bone res- scaffold was implanted in the lumbar transverse defects in
toration in comparison to gelatin porous structure control rabbit model and then SMF were applied. The MNP scaffold
without SPIONs. It is notable that the endocytic SPIONs with application of an SMF persuaded more osteogenesis,
stimulated the osteogenic and angiogenic performance of new bone formation and remodeling in the rabbit defects
the cells result in better bone regeneration (Gu et al. 2013). (Hu et al. 2018). Along with stem cells and scaffolds, growth
The aggregation of SPIONs as a result of magnetic fields factors delivering are a vital method in bone tissue regenera-
may change their biological impression. Definitely, decrease tion. MNPs have the potential for using as a delivery tool for
in cell uptake followed for the reason that agglomeration of biological mediators for instance drugs, chemotherapeutics,
the particles as a result of substantial variations in mutually antibodies, peptide, oligonucleotides, and growth factors
the size and zeta potential. Furthermore, external magnetic through magnetic fields. For example, gene delivery using
fields may affect the biological properties of SPIONs such MNPs possibly will be multifunctional, performing utilities
as therapeutic/toxic effects. In a research, (­ Fe2+/Fe3+)-doped that contain the identification, healing and visualization of
HA (FeHA) nanoparticles in cultures with osteoblast-like the disease at the same time. Consequently, magnetic-based
cells in the absence, or presence, of an SMF were investi- gene delivery is extremely promising method for stem cell
gated. Application of external magnetic field to FeHA lead therapy (McCarthy et al. 2007).
to a substantial cell growth, proliferation and more osteo-
blastic activity as a result of the tremendous biological Bone/biomaterials interface studies
impacts of HA and the partial iron content. Consequently,
the variations in the biological characteristic and endocy- For the effective integration of implants or scaffolds for
tosis of the cells, created by the MNPs using external mag- tissue regeneration, cell adhesion to biomaterials is a vital
netic field, may pointedly improve the cell performance and necessity. Adjusting cells–scaffolds communications seems
bone renewal abilities (Tampieri et al. 2014). Stem cells have of most important to affect succeeding cell biological pro-
excessive potential for tissue repair. Magnetically labeled gressions for instance attachment, proliferation and differ-
cells have the potential application for bone tissue regenera- entiation (Tormos 2016). Numerous reports show that the
tion, containing cell targeting and cell patterning. SPIONs adhesion of integrins in bone cells including osteoblasts
are able to operate as an ideal labeling and tracer tool for and osteoclasts to the extracellular matrix is vital through
MSCs. MNP intake into the cells and make them manage- the bone repair (Puleo and Nanci 1999). Bone extracellu-
able and manipulated by external magnetic field. In a study lar matrix proteins arbitrate the biological function of cells
implantation of magnetically labeled MSCs were employed through moderating their milieu. Motivation of the attach-
to regenerate serious chronic osteochondral traumas, expo- ment, proliferation and differentiation of the bone cells are
sure to an external magnetic field, considerably produced determined by the part of the superficial characteristics,
new chondrogenic tissues (Li et al. 2018). chemical composition, electrostatic charge, texture, geo-
Dip coating technique was used to fabricate magnetic metrical configuration, roughness and smoothness, of the
HA/collagen scaffolds. The magnetic scaffolds support replacement (Venkatesh and Sen 2017). The ceramic bio-
the attachment and proliferation of hBMSCs, and motivate materials may be abrasive and consequently, it is crucial to
osteoblastic differentiation. The results were along with a avoid them in uncontrolled damage neighboring to articu-
different study on MNP-HA magnetic scaffolds. lar surfaces. Bioglass ionic extracts and surface exchanges
In another study, nanofibrous γ-Fe2O3/HA/polylactic stimulate the proliferation and differentiation of osteoblasts
acid was fabricated. This scaffold improved the prolifera- and the fabrication of the primary phenotypic biomarkers
tion of osteoblastic by reason of the SPION integration (Kim (Abid et al. 2017, 2016).
et al. 2006). In a current research, an injectable calcium The cell activities are regulated by biodegradable poly-
phosphate/SPIONs cement has been developed by mixing mers with properties such as chemical structure, polymer
with a SPION. Osteogenic differentiation and bone matrix ratio of PLA or PGA for example, molecular weight and
mineral synthesis by the cells was similarly improved two crystallinity. Polymer degradation products for instance cata-
folded in comparison to samples without SPIONs (Xia et al. lysts, additives, byproducts and residual monomers that led
2018a). ­Fe3O4 nanoparticle/bioactive glass/polycaprolac- to an inflammatory reaction and influence the cell attach-
tone ­(Fe3O4/MBG/PCL) scaffolds was fabricated using a ment, cell survival and proliferation (Puppi et al. 2010).
3D printing method. The results indicate that cell growth Composite structures present tolerable physiological and
on the F ­ e3O4/MBG/PCL scaffolds was greater than non- mechanical performance such as the characteristics and
magnetized control sample (Zhang et al. 2014). In vivo morphology of cortical and trabecular bone. Signaling fac-
results using rabbit model confirmed that the PCL/FeHA tors can be included to bone composites to stimulate cell
scaffolds were enhanced bone regeneration in comparison to behavior and favor bone repair. Several factors impact on

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Progress in Biomaterials

the release of growth factors, for example the surface charge of the active molecules at a reliable and useful amount.
and chemistry of composite, geometry, dimensions, poros- Besides, cell-based approaches can be utilized for big and
ity, wettability, crystallinity, the rate of degradation. The complicated bone defects. The efficient clinical treatment
growth factor release could be regulated by diffusion, exte- demands more controlling phases for future developments.
rior motivation, enzymatic/chemical response (Muzzarelli
2011). The cell attachment to biomaterial and their follow-
ing performances can be influenced by surface features for Compliance with ethical standards 
instance topography, hydrophobicity, charge, chemistry and
special surface energy (Von Recum and Van Kooten 1996). Conflict of interest  Authors did not receive research grants. The au-
thors declare that they have no conflict of interests.
These all affect the conformation, alignment and amounts
of adhesion proteins including vitronectin or fibronectin Ethical statement  This article does not contain any studies with ani-
that facilitate the interfaces among cells and biomaterial mals performed by any of the authors.
(Place et al. 2009). Lithography, colloidal particle adsorp-
tion, micro-contact printing, novel polymer preparations and Open Access  This article is distributed under the terms of the Creative
self-assembled monolayers are all employed to analyze the Commons Attribution 4.0 International License (http://creativecom-
interactions among cells and biomaterials at the micro- and mons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
nanometer scale (Ma et al. 2007). These methods may be uti- credit to the original author(s) and the source, provide a link to the
lized to regulate the topographic properties, micrometer or Creative Commons license, and indicate if changes were made.
nanometer ridges, grooves pits, islands, holes. Some studies
have revealed improved bone–biomaterial interactions with
a high surface roughness. In a study, PLA-polystyrene films
with porous of about 45 nm caused human fetal osteoblasts References
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