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73 (); 147-158
doi:
10.1016/j.jor.2025.11.041

Programmable materials: A comprehensive review on shape memory polymers for orthopedic applications

, , ,
a Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru, Karnataka, India, 572103
b Department of Mechanical Engineering, Siddaganga Institute of Technology, Tumakuru, Karnataka, India, 572103
c Department of Mechanical Engineering, National Institute of Technology Karnataka, Surathkal, Karnataka, India, 575 025
d Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India, 560054
e Department of Mechanical Engineering, SJCE, JSSSTU, Mysore, Karnataka, India, 570006

⁎Corresponding author: Anupama Chalimeswamy. anupama83@sit.ac.in

Received: , Accepted: ,
Professor P K Surendran Memorial Education Foundation
Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Shape memory polymers (SMP) are smart, active polymers, which can significantly change their properties by external stimuli such as heat or temperature, pH, electric and magnetic fields. SMPs take advantage over traditional metal alloys due to their properties like degradability, biocompatibility, non-toxic, cost-effective, and low immunogenicity. They create suitable microenvironments for the tissue regeneration in the host cells. Hence, shape memory polymers are programmable promising materials in orthopedic applications in which implants must withstand large strength and flexibility. Shape memory and self-healing are the two fundamental properties of polymers considered in the design of scaffolds materials. Programmable biomaterials includes, biologically responsive, chemical and physical responsive polymers suitable for bone tissue engineering. This review deals with an overview about the generation of metal shape memory alloys/ceramics/shape memory polymers/self-fitting scaffold materials used in orthopaedic therapy. And also osteobiology, properties of SMPs, FDA approved/clinical usage of SMPs, use of Artificial Intelligence (AI) based strategies for bone scaffolds, recent trends, and future prospectus were addressed.

Abstract

Graphical abstract

Image 1

Keywords

Shape memory polymers
Bone tissue engineering
Scaffolds
Osteobiology
Implants
1

1 Introduction

Bone/joint degenerative problems are affecting people worldwide. The treatment for bone defects itself is a socioeconomic challenge. 1 Any injuries/trauma, autoimmune and age associated diseases related to bone can cause long-term healing approach and pain. Approximately 15 million bone fractures/year were reported annually in US, which includes the complications associated with knee replacements, hip replacements, traumatic fractures and osteoporotic cases. 2 Bone and joints require the highest mechanical strengths for daily activities in the body. 3 Orthopedic implants are classified as temporary fixatives and joint replacements. Includes, screws, plates, nails, external fixators, and hip implants, etc. to various parts of the body like hip, knee, ankle, shoulder and elbow joints. 1 From previous decades, the smart materials like shape memory alloys (SMAs), ceramics and polymers, were instigated for orthopedic implants. 4 U.S. Food and Drug Administration (FDA) has permitted to use different metals/ceramics/polymers/composites for the bone treatment. 5 Metal implant materials are continued to be used and constantly modernized for orthopedic use. The current trend in orthopedic implants is toward shape memory polymers, because of their shape memory behaviors. 6 Compared to SMAs, SMPs have great shape memory properties. SMPs are lighter, soft, biodegradable, with good elongation properties. They change its shape and size according to stimuli given by external agents like temperature, pH, light, solvents, and electricity. 6 The current reports suggest, there is a substantial growth for shape memory polymer market across the globe reaching a growth rate of 21.5 % from 2021 to 2027. 7 The selection of shape memory biopolymeric implants depends on the severity of the bone fracturs. The design/selection of shape memory polymers depends on not only physicochemical properties of the polymers but also based on the interaction with the host cells (biocompatibility). 8 The biocompatibility of SMPs is described in terms of mechanical biocompatibility (the stability of implant material), biological compatibility (integrating behavior of implant with the tissue), histocompatibility (inflammatory response), and blood compatibility (ability of biomaterial to promote healing). 6 Hence a good biopolymer should possess all the above biocompatibility properties.

This review summarizes the evolution of SMPs used as implants for orthopedic applications and covers the advantages of polymers over metal implants. Also covers the orthopedic applications of SMPs as a scaffold material in tissue engineering, use of artificial intelligence in development of bone scaffolds and future prospectus. Several research have been reporting on shape memory polymeric materials with the prospective of material science and medical applications. Here, we focus on the breakthroughs of material science in the evolution of SMPs for orthopedic usage.

2

2 The saga of generations of implants: metals/ceramics/polymers

2.1

2.1 Metals

Bio-inert metal implants were designed and fabricated using pure metals or alloys; using steels, titanium, nickel, aluminum, cobalt, and chromium, etc. 4 The metal-based alloys were used in the form of screw plates and hip nails and offers good mechanical strength, wear resistance, biocompatibility. Metal surfaces are coated with hydroxyapatite, extracellular matrix (ECM), ceramic magnesium, and chitosan etc. to interact with surrounding tissues. 9 Another approach is by spraying/coating the surface of biodegradable metals to make into more bio-interactive materials. 10 Cobalt based alloys (cobalt-chromium-molybdenum) are used in prosthesis of hip joints because of its biocompatible and abrasion resistance properties. 11 Nickel-Titanium (Nitinol) alloys are considered as superior and stronger metal devices with excellent biomechanical properties like less density, low modulus value, and unaffected to corrosion by the body fluids, on the other side, Nickel is known for its toxic behaviors. 12 Hence, Nitinol is coated with titanium oxide to reduce the toxicity caused by the leakage of nickel ions. 13 Biodegradable and non-toxic metals like magnesium and zinc are used in successful bone fixing materials. Components like silver, copper, zinc, cerium, are used as adsorbing coating layers to induce osteogenesis and exhibit antimicrobial effects by killing microorganisms by various mechanisms. 14

2.2

2.2 Ceramics

Bone itself considered as bio-ceramic composite of calcium phosphate. Various Porous ceramic materials containing calcium and phosphorous are used for bone regeneration. 15 Ceramics have been used clinically for several decades for their biocompatibility and toughness properties. Alumina, zirconia, polyethylene, bioactive glass (BGs), glass-ceramics and composites of calcium phosphates are good examples as ceramics, widely used in hip joints, femoral heads or acetabular cups. 16 Bio-active ceramics are biocompatible and help in the regeneration of bone tissues. 17 Bio ceramics were replaced by metallic implants for hip prostheses, acetabular cups etc. High density alumina is an excellent ceramic material with good corrosion resistance, high strength as well as biocompatible. 18 High porous ceramics are developed to provide ingrowth of bone cells, but themselves causes decrease in mechanical strength due to large porosity and limited flexibility. 19

2.3

2.3 Polymers/shape memory polymers and its types

Substantial advancement has been made in recent decades in search of polymeric materials/composites to enhance biological properties. 20 Bone tissue engineering is an emerging area in regenerative medicine, that aims to provide a living substitute made by the polymers that acts as a mechanical supporting scaffold. 21 At the same time, the emergence of scaffolds for tissue engineering applications has enhanced the diversity in applications of SMPs. Scaffolds are the three-dimensional supporting porous matrix prepared by natural/synthetic polymers, helps in tissue regeneration. 22,23 These smart scaffolds closely mimic the natural extra cellular matrix (ECM) and help in osteogenic tissue regeneration. 24 Synthetic and natural biopolymers having shape memory effects have been employed as a trend in orthopedic and bone tissue engineering. Biopolymers are broadly classified as natural polymers (proteins, polysaccharides and nucleotides), microbial polymers (PHA; polyhydroxy alkenoate and PBA; phenyl butyric acid) and biopolymer blends (derived from natural materials). 25 Medical grade polymers are mostly synthetic polymers such as silicone, polyethylene (PE), polymethyl methacrylate (PMMA), polypropylene, silicone, and polyurethanes (PU), Polyglycolic acid (PGA), poly lactic acid (PLA), polyhydroxy valerate (PHV), polydioxanone (PDS), poly (ε-caprolactone) (PCL), polyhydroxy butyrate (PHB), poly-Ortho ester, chitosan, hyaluronic acid and hydrogels etc, are considered as first-generation shape memory polymers. 26

SMPs are responsive to heat or temperature, water, electricity, light or magnetic stimuli. 27,28 Polycaprolactone diacrylate (PCLDA), poly (glycerol dodecanoate) acrylate (PGDA), powder bed fusion (PBF), Pellithane are very good SMPs for in vitro/in vivo regeneration of osteoblasts. 29 Polymethylmethacrylate (PMMA) was the first synthetic SMP used for corneal implants. 30 PMMA blended by ceramic glass, antibiotics etc. also shows significant drawbacks in controlling infections due to necrosis and tissue damage. 31 Because of low density, polymeric nature, resistance to abrasion behavior, and biocompatibility/histocompatibility, 26 single responsive-SMPs are associated with many challenges and limited scopes. Even having advantages associated with chemical structures and kinetics of degradation with the use of polymers in joint prosthesis, also have disadvantages like shrinkage of material size and poor biological response. 32 For example, silicones were effectively used in the treatments of rheumatoid arthritis and reduces pain 32,33. But the flexible nature of these implants leads to fractures and associated with bone erosion, laxation, graft abrasion. 34 Due to many disadvantages in first generation SMPs, second generation SMPs evolved with the ability to enhance their physicochemical properties and maintain tissue microenvironment. Second generation/third generation shape memory polymers comprise improved polymers/composites with control over their breakdown, absorbability, degradability behaviors, and tissue regeneration. 35 These SMPs show good surface bonding with the surrounding tissue and help in the healing process. New generation biopolymer implants are not poisonous or mutagens, hence used in preparation of anchors. 36 Poly-ether ether ketone (PEEK) is such a scaffold polymer shows high strength, good wear resistance, and shows similar elastic modulus concerning bone of humans, but displays less interaction nearby tissue surroundings due to its bio-inertness, hydrophobic and low surface energy behavior, this led to implant failure. 37 Recent reports suggest, the surface modification by adding hydroxyl, sulphate groups may enhance the adhesion, spreading and proliferation of osteocytes. 10 Several strategies were adopted to enhance antimicrobial properties of PEEK polymeric materials for animal trials such as suture materials, rotator cuff injury and ligament surgery. 35 For an illustration, PEEK scaffolds coated with a sandwich (pDa-Ag-pDa) of materials containing polydopamine (pDa) and silver nanoparticles (AgNPs). The bacteria encountered by the Ag2+ ions containing scaffold under acidic microenvironment. 38 Simultaneously, Ca2+ and PO34− ions are released to initiate osteogenesis process. This was an evidence of inducing osteogenesis by surface modification of SMP scaffolds. 39 Similarly, Yao et al. developed pH responsive programmable hydrogels made by gelatine methacryloyl (GelMa) with oxidized sodium alginate (OSA) to release gentamicin sulphate antibiotic. 40

The SMPs include multi-functional programmable materials like; nucleic acid based biomaterials, electrically responsive biopolymers, programmable bioactive polymers, nanomaterial based polymers, surface engineered implant based biomaterials, and stimuli responsive based biomaterials. Moisture/water-sensitive-shape-memory polyurethanes (SMPUs), shape memory fibers are used in biomedical applications. 41 The group of biomaterials/biopolymers used in orthopedic/bone tissue engineering is shown in Fig. 1. For orthopedic applications biodegradable SMPs (BSMPs) are preferred with the properties like weightless, lesser density, good flexibility, non-toxic and easy processability. Adding to this, manipulation of physical properties such as porosity, micro and nanostructures with respect to mimic the biological structures. 42 For the applications of orthopedics implants/scaffolds preparation requires shape-memory effects, degradation to give non-toxic compounds, and mechanical strength for the developing tissue near the bone. Fourth generation shape memory polymers includes, Polylactides, polyglycolides, lactone polymers have self-healing properties with musculoskeletal repair. Polymers include poly lactic acid (PLA), poly (L-lactide) (PDLA), poly-d, l-lactic acid (PDLLA) are broadly used in scaffold preparation for bone tissue regeneration. 43 Bao et al., mentioned about the synthesis of scaffolds using poly lactide-co-trim ethylene carbonate (PLMC) in different ratios, and reported that, proliferation and osteoblastic biocompatibility concerning the PLMC scaffold is safe for bone regeneration. 44 Before selecting any SMPs implants/scaffolds, it is required to study Osteobiology and its mechanism.

Types of polymers; natural and synthetic polymers with its advantages and disadvantages. Shape memory polymers with its advantages and disadvantages.
Fig. 1 Types of polymers; natural and synthetic polymers with its advantages and disadvantages. Shape memory polymers with its advantages and disadvantages.
3

3 Osteobiology

Study of Osteobiology is the major priority to understand the behaviors of implants made by metals/non-metals like SMPs in the host. 45 Bone is the supporting framework to the internal organs, serves as storage of minerals (calcium and phosphate) and produces the blood, its constituents by a process called hematopoiesis. 46 Bone is made by collagen (called as ossein) as organic component and hydroxyapatite (compound of calcium) as inorganic component. 47 Two types of bone tissue are present namely, compact bone and spongy bone. 48 Compact bone is rigid and forms the outer layer of the bone called cortex. Spongy bone is soft (or called trabecular bone) is present internally as bone marrow and has high surface to volume ratio. Bone is associated with muscle soft tissues and connective tissues. Tendons, ligament and cartilage are associated with bones to enable mechanical stress without causing damage to the musculoskeletal system. The hard bone and soft connective tissue interface is less than 1 mm. 48

Bone itself is considered as smart biomaterial because of its composition and structural remodeling to combat mechanical stress. 49 Bone cells have self-healing behaviors. For healing process, requires healthy osteogenic cells. 50 For regrowth, respective growth factors will activate the cellular metabolism. Recent studies reveals the use of vascular endothelial like growth factor (VEGF) and Hypoxia-inducible factor-1 alpha (HIF-1α) induce angiogenesis. 51 The healing mechanism also depends on implant material's topology and chemical structure, finally inducing osteogenesis by recruiting blood cells and mesenchymal stem cells (MSCs). Bone fracture healing is affected by aging, osteoporosis, bone density etc. Several case studies reported delaying the healing process in osteoporotic conditions in humans. Mainly, osteoporotic individuals with post menopause conditions in women are having poor growth rate and low differentiation of stem cells (MSCs) compared to young womens. 52 Nonunion fractures are complicated, and FDA defined it as, the presence of unhealed fractures for a period of 9 months. Any bone fracture is associated with multifactor, such as biological (blood supply, drugs given during treatment, medical history of patient) and mechanical factors (impact of fracture, stress at the fracture site). Thus, healing of the fracture is associated with many biochemical processes. Intramembranous and endochondral ossification involves formation of bones by osteoblasts. In comparison, endothelial ossification is observed in long bones. 53 Excess of ROS create oxidative stress and associated with delayed in bone regeneration. 54 Hence a thorough understanding of the process of bone regeneration is required for the treatment. Resveratrol (a poly phenol antioxidant) enhances the osteogenic potential of bone marrow mesenchymal stem cells (MSCs) and used for the bone repair treatments. Cai et al. demonstrated the use of resveratrol liposomes in surface functionalized with chitosan (CS-Res@Lipo) and HAMA@HepMA hydrogel microspheres showing osteogenesis behavior. BMP-2 (Bone norphogenetic protein-2) is released programmatically (BMP-2 is a key molecule for osteogenesis) and stimulate the DNA synthesis. 55 Such type of programmable biomaterials dynamically responding at the injured areas in the bone. Designing a specific bone implants/scaffold requires mimicking the biomechanical properties of native tissues with the bone. Osteochondral interface (interface between ligament/tendons with bone or bone with cartilage) has highest tendency with acute or long-term injuries. 56 Silk fibroin (SF) based scaffold is mimicking the natural cartilage. SF can be programmed in order to sustatin release of bioactive molecules to improve cartilage resurgence. The current treatments with the implants/surgeries may not meet the natural interface. The restoration or regeneration of interface tissues remains a significant task for orthopedics. 57 Customized, porous fabricated GDM/CeHA@CA scaffold (Gelatin methacryloyl with citric acid-modified cerium-doped hydroxyapatite nanowires (CeHA@CA)) promoted the bone repair in 12 weeks by slow release of Mn2+ in rabbit bone defects. The slow release of Mn2+ promotes immunomodulatory response by down reulation of MAPK pathway on the other side, the release of Ce3+/4+, Ca2+ and PO43− from the cerium-doped hydroxyapatite nanowires promotes angiogenesis and promotes osteogenic differentiation. 51 Osteo-genecity/conduction/induction (Fig. 2) are the terms needed to comprehend the physicochemical behavior of SMPs implants under in vivo condition. 58 Osteoconduction means, the implant material (scaffolds) should facilitate the regeneration of new cells. Osteo-induction means, the capacity to encourage the attachment of osteoblastic cells with the selected biopolymeric scaffold/implants. After attachment, the stem cells undergo differentiation to attain morphology of osteoblastic cells. This process is termed Osteogenesis (shown in Fig. 2). 58 Bone regeneration is associated with several cells like osteoblasts, myogenic cells and stem cells. 59 Stem cells (mesenchymal stem cells, adipose stem cells etc.) undergo differentiation to form osteoblasts based on the osteo-induction condition. Various growth factors are loaded with polymers to enhance cell/tissue growth in tissue engineering. 60 Slowly, the polymers undergo degradation/reabsorbed and substituted by neo tissue (new tissue) near the damaged part. This above phenomenon is necessary for developing and regenerating bone tissue. 61 A good scaffold must be designed based on the following criteria: first; scaffold must bind to bone tightly to establish osteo-integration and second the mechanical stimulation exhibited by SMP based scaffolds. 62 Once scaffolds are inserted into the critical sized defects, stabilization is needed. Improper secretion leads to micromotion at scaffold-bone interface. 63 Micromotion causes accumulation of debris from the implant-bone interface. Finally elicits inflammatory response and osteolysis. 64 Further the properties and advantages of SMPs are mentioned in the next section.

Biomechanical properties of shape memory polymers behave as ideal materials to induce osteogenesis. 1. Osteoconduction: Scaffold is facilitating the support for angiogenesis and cell attachment. 2. Osteoinduction: Induces differentiation of undifferentiated cell to form osteoblast. 3. Osteogenesis: Bone regeneration and development of MSCs.
Fig. 2 Biomechanical properties of shape memory polymers behave as ideal materials to induce osteogenesis. 1. Osteoconduction: Scaffold is facilitating the support for angiogenesis and cell attachment. 2. Osteoinduction: Induces differentiation of undifferentiated cell to form osteoblast. 3. Osteogenesis: Bone regeneration and development of MSCs.
4

4 Properties of SMP scaffolds

The criteria for selecting biopolymeric implants/scaffolds for bone tissue regeneration are, it must be non-toxic, biodegradable (reabsorbed at the same site), and biocompatible. For the use of clinical studies, SMPs must have the properties like; mechanical properties, biocompatibility, high abrasion resistance, high corrosion resistance, non-toxic, and osseointegration. 10,65 The biodegradable polymers easily get hydrolyzed by the enzymes and degrade without causing complications associated with secondary surgery. But has drawbacks like strength and mechanical stiffness, unfavorable tissue responses, foreign body responses, late tissue deprivation reactions, crystallinity, and hydrophobicity behavior to prone infections. 66 Nano material-based SMPs support the osseous structures with pore sizes at nano levels, required for cell migration. 67 Additionally gives optimal mechanical support by acting as biochemical surface markers to trigger many signaling cascade system involved in healing bone defects. 50 Hence, many SMPs are used as nanostructured materials to treat irregular bone defects to withstand compressions. 68 Apart from understanding the physicochemical properties of SMPs, it also leads to study of the tissue engineering concepts like tissue organization, angiogenesis, supply of nutrients, cell signaling pathways, growth factors, and peptide interactions etc. 69 All above cellular events are crucial for a successful tissue regeneration after insertion of implants/prosthesis in bone fractures.

SMPs are made by crosslinked polymers, the types of cross links dictate the shape memory effect and mechanical behavior. The in vivo recovery process ultimately depends on the interaction between the implants and the surrounding tissue microenvironment. 70 Hence, an ideal polymer implant should act as a thin interphase for the attachment of the host cells. The change in topography or stiffness of SMP scaffolds can promote osteogenesis. 26 The ideal bone tissue engineering SMP scaffolds should have great biomechanical properties (as mentioned in Fig. 2) like biocompatibility, good degradation behaviors, suitable surface interaction, porosity, resistance to compression, young's modulus, tensile strength and fatigue. 71 Many SMPs have been developed with similar properties of soft tissues. For example, SMP made with combination of poly (ethylene glycol) diacrylate cross linked with methyl and isobornyl acrylate shows swelling behavior in PBS, this shows similar mechanical property like in vivo tissues. 72 Once tissue regeneration starts, the SMPs degrade and readily be absorbed by the surrounding cells without causing any inflammatory effects. 73 Phase transformation initiated according to type of stimulus to attain stable structures, hence gains mechanical strength. Entropic energy is stored in a stable structure. As soon as, stimulus is removed, the entropic energy is released from stable structure quickly to attain its original shape with weak non-covalent interactions. 74

SMPs are verified to have biocompatibility, degradability and mechanical properties. As well as cellular events like osteoblasts adhesion, proliferation and osteogenic differentiation. A classic example of Tseng et al. includes, seeded human adipose derived stem cells (hASCs) on fabricated SMP scaffold prepared with a combination of acrylate and thermoplastic polyurethane (TPU). This was cultured at 30 °C for five days to initiate osteogenesis. Then, scaffold was placed at 37 °C to switch from compressed pore structure to permanent open pore structure. Cells were continued to culture for 23 days in the same scaffold and showed the osteoblast differentiation. 75

SMPs turn on to different stimulus under both in vivo/in vitro. Types of stimuli include physical, chemical, and biological stimuli, as shown in Fig. 3. Physical stimuli comprise temperature, magnetic, ultrasound, electrical etc. Recovery kinetics of SMPs is critical and explained concerning temperature as one of the stimuli. 76 SMPs are tunable concerning the different temperatures. Transition temperature (Ttrans) is another important physical property of SMPs. Ttrans should allow the recovery of native shape (usually ranging from 10 to 50 °C). Ttrans should come within the range of body temperature for any orthopedic applications. Thermal responsive SMPs operate at different temperatures. 77 Chemical stimuli like chemical signals within the microenvironment include the polymers pH, redox, ionic, solvent, and surface chemistry. 78 SMPs are programmed according to the type of microenvironments present in the diseased tissues. For example, pH sensitive SMPs are altered to release drugs or therapeutic products accordingly concerning the site's pH change. Acidic functional groups such as -COOH and -SO3H are coated on polymers. Hyaluronic acid, chitosan, alginic acid, gelatine, and poly l-glutamic acid are natural acids. 79 Finally, biological stimuli include the biological clues present at the site of diseased microenvironment. The biological clues are enzymes, biomolecules, generation of Reactive oxygen species (ROS) etc. gets deregulated due to pathological state. Researchers are trying to target biological molecules using smart SMPs. 80 These bioimplants slowly degrade and reabsorbed by the host cells. There are three critical stages need to attain by SMPs, first is the native stable state (original 3D network arrangement), second is reversible state (reversible structure according to stimulus) and third is responsive stage (switch between native and altered 3D arrangement). 81 Non-permanent and biodegradable SMP implants can be designed so that, as soon it is inserted to patients, they could give temporary mechanical support and degrade itself with the rate of tissue formation. Polymers such as PFTE, PLA and polyvinyl acetate ethylene (EVA) are examples of thermos responsive SMPs. 82 The combination of PLCL and PLGA based SMPs has 100 % recovery rate at 37 °C. 41

Biological stimuli such as enzymes/proteins, Biomolecules, Reactive Oxygen Species etc.; Physical stimuli such as Temperature, light etc., and Chemical stimuli such as pH, Ionic interaction, solvent etc. to induce self-filling and self-expanding Shape Memory Polymers.
Fig. 3 Biological stimuli such as enzymes/proteins, Biomolecules, Reactive Oxygen Species etc.; Physical stimuli such as Temperature, light etc., and Chemical stimuli such as pH, Ionic interaction, solvent etc. to induce self-filling and self-expanding Shape Memory Polymers.

In contrast, polyether urethane scaffold is having transition temperature of 70 °C, but it can be distorted and fixed at different temperatures ranging from 40 to 60 °C. With the increase in distorted temperature, recovery was slow. 86 The cost of biodegradable implants should be cheap compared to metal implants. 64 Orthopedic SMPs are designed to treat bone, ligament, tendon, and cartilage. Implants/surgical interventions are suggested in bone and joint degenerative and inflammatory problems (rheumatoid arthritis, osteoarthritis, etc.). 87

4.1

4.1 Shape memory polymers vs shape memory alloys

Shape memory alloys are well-known as safe materials for orthopedic use and have retrieval behaviors concerning stimulus, hence known as shape memory effect. Many new alloys with Mg2+, Zn+ and Fe2+ combinations show super biocompatibility, good corrosion and wear resistance. 83,84 Problems associated with fatigue and more hysteresis property of shape memory alloys also have negatives due to less elasticity and bio-efficacy. 85 In addition, secondary surgery is required to remove the metal implants after healing, this may create colossal pain for the patient and treatment is expensive. Secondary surgery to remove permanent implants materials are highly associated with necrosis and severe infections. 86

Further, minute fractures associated with soft bone tissues (cartilages) are difficult to treat with metal-based alloys. All implants related to metal alloys and ceramics have been proved efficacious in clinical trials but are associated with several drawbacks. 87 It includes expensive alloys, complexity in thermo-mechanical behavior, residual stress in thin films, temperature dependent effect, low operations speed, stiffness/flexibility, etc. 87 Another hindering point is the corrosion properties of the alloys for in vivo applications. Alloy-metal implants may release toxic, cytostatic, carcinogenic metal ions such as Ni, Ti, Co, Cr, etc. in the body to cause adverse effects and failure in the implants. 88 Still progress is needed in design and optimization to enhance the surface adsorption properties of metals. Many failures in the last 40–50 years were reported concerning hip replacement surgeries. 89 Looking to an ideal implant material, it does not exist for long term usage. The failure of implants is associated with the biology of bones and clinical factors. Porosity of implant materials has an important role in osteointegration. 90 For example, Wei Zhao et al. worked to design 3D printed shape memory scaffold composites using polylactic acid/Fe3O4 to treat bone defects. 91 This design was porous (lotus root microstructures inspired) with shape memory effect with good mechanobiological advantages to use for bone regeneration. A more revolutionary view was to prepare customized implants related to the osteobiology of patients for great stability and lesser failures. The potency of toxicity and leaching effects of metals are more. This led to a rise in inflammatory or allergy reactions and associated with infections. For example, it was reported that titanium ions cause yellow bile syndrome and aluminium causes osteomalacia conditions respectively. 61 Hence, a thorough investigation is needed to improvise the biological properties of metal implants.

Traditional SMPs are made by synthetic materials, inadequate osteogenic properties, deprived contact with nearby bone tissues and associated with surgical complications. 92 Hence, SMPs are developed with different blends, combinations, composites, carbon nanotubes, ceramics, and biodegradable metal alloys. These were porous, stable with biomechanical behaviors and show excellent biocompatibility leads to neo-vascularization of bone under in vivo.6

4.2

4.2 Why shape memory polymers for orthopedic applications?

Decades of research have witnessed for the better understanding of SMP scaffolds as special features to initiate cell growth and proliferation. Because of the scaffold's porous nature and deformation property, even small, irregular bone defects can be treated. 93 The scaffold microenvironment could facilitate regrowth, differentiation and morphogenesis. SMPs-based scaffolds can be delivered into the host body by non-invasive approaches. For example, 7SMP-HA (Hydroxy-Appetite) based scaffold is more porous near to 80 %, even big sized scaffolds can be passed through syringe needle. Because of porosity, it contributes to shape deformation and tissue invasion. 94 The design of a porous SMP scaffold involves the following steps: preparation, fabrication, characterization, cell adhesion and proliferation behaviors, osteogenic differentiation. 95 And finally, degradation of porous scaffold under in vitro and in vivo conditions is possible. By exhibiting the good property of orthopedic shape memory polymeric implants, along with biological unresponsiveness behavior, it also helps in the healing process. Collagen, fibrin, and chitosan, considered natural polymers, show excellent osteobiology and mechanical properties compared to bone autografts. 96 Coated/adsorbed materials are used to enhance the osteoconductive and osteoinductive properties. For example, Calcium phosphate (CaP) is coated on the surface of hydroxyapatite implant targets to improved osseointegration between the biopolymer and tissue layer. The CaP based coatings resemble the natural composition of bone. 97

Additionally, many inorganic (boron nitride), organic (gelatine, chondroitin sulphate and protein isolates etc.) compounds are applied as a coatings to increase osteointegration. 98 Healos (used as autografts), a commercially available natural matrix prepared using Type 1 collagen and hydroxyapatite and fibrin, are used in tissue engineering applications. 99 Polyurethane (PU) with aniline trimer (AT) based scaffold has self-fracture healing capacity and osteogenic potential both in vitro and in vivo conditions. 100 Compressed form of SMPs during implantation may cause micro-cracks if the material is not flexible. This defect may lead to implant failure and associated problems to the patient. 101 However the innovative design of SMPs shows self-healing behaviors at transient temperatures like 40 °C, this is due to the synergic effect of shape memory properties and the respective functional groups associated with it. 102

In vivo biocompatibility tests involve inflammatory reactions in the host tissues. Sectioning and staining of the implanted interface give a valuable clue. Hydrophobicity and bio inertness behaviors of SMPs had prevailed by functionalization with specific biomolecules to design altered biocompatible surfaces. One such classic example includes plasma immersion ion implantation (PIII) and attachment of collagen on polyurethane based SMPs showed increased wettability behaviors and biocompatibility. Histopathological and immunohistological studies confirm neovascularization, proliferation and production of cytokine. 103 PCL based SMP scaffold coated with polydopamine (PDMS) shows better oesteo-generation. Certain SMPs are coated with active agents to target antigens or macrophages and microorganisms by slow release of drugs. The establishment of neo-organization in a scaffold material is influenced by density of seeded cells/growth factors etc.. 104 The scaffolds should have potential to regenerate, to cover damaged tissue. Osteointegration is a challenging issue for the attachment of biopolymer implants. Biocompatibility of polymers is also influenced by osteogenic factors. Some polymers are tagged/decorated with several functional groups of materials to enhance its biological activities as well as biocompatibility. The materials include nano-coatings, nanotubes, hydrogels, organic and inorganic nanoparticles. For example, in vivo studies in the rabbit femoral defect model, polyurethane/HA SMP foam was inserted. Later, SMP was triggered to expand to fit in the femoral defect within 60 s. Bone mineralization was observed surrounding SMP foam and gradually increased even after 12 weeks. Histological studies also confirmed about neovascularization and bone remodeling. 105

Several reports suggest such modifications in SMPs. Yuxin Zhang et al. reported the use of growth factors (Concentrated growth factors (CGFs)), loaded hydrogels for the induction of osteogenesis process. 106 Like this, bioactive exosomes, hydroxyapatite granules are loaded with drugs to induce osteogenesis to repair bone defects. 107,108 Both natural polymers and synthetic polymers like collagen, hyaluronic acid, chitosan, gelatine, silk fibroin PEG, PVA, PNIPAm, and PLGA are used in preparation of response stimuli smart hydrogels for bone therapy and regenerative medicines. 109 Nanomaterials show great potentiality in orthopedic applications, used in many ways like, nano-coatings, nanostructures on the implants by functionalization etc. Junchao Luo et al. have demonstrated the osteogenic character of cerium oxide nanoparticles (CeO2 NPs). CeO2 NPs stimulates the MSCs to secrete vascular endothelial cells (VEGFs), helps in mineralization and homeostasis in bones. 110 As well as cerium ions (Ce 3+) based injectable microsphere porous hydrogel (P-GelMA-Ce@BMSCs) were designed to promote osteoblast activity. 111

Scaffolds/biopolymeric materials are decorated with tripeptide RGD functional groups to enhance ECM production and increase ligament cell attachment and proliferation. Hydroxyapatite/collagen type 1/chitosan scaffolds showed good biomechanical properties and supported osteogenesis in a rabbit model with maxillofacial mandible defects. 112 Many SMPs act as good in vitro and in vivo models for orthopedic applications. Typically, 2D substrates systems have their own advantages and limitations compared to 3D cultures. 113 2D substrates may be programmed with large pore size, allowing for cell growth at the interior place of scaffolds. A shape tunable scaffold facilitates attachment of cells. To make cell compatible SMPs, cell adhesive peptides were decorated on the surface. 114 An acrylate-poly (ethylene glycol) was decorated with a chain of amino acids like Gly-Arg-Asp-Ser and this macromer was cross linked with polyethylene glycol gives biodegradable shape memory behaviors with no toxic effects. 115

Further, 4D printing of orthopedic implants are making trends for knee replacements, joints fractures etc. In this technology, the smart polymers print several layers of scaffolds using a computer-aided design drawing (CAD) model. The printed material may change its shape according to the stimulus after some time under in vivo condition. The 4D printed SMP scaffolds are advantageous over 3D and, 4D models because of its excellent durability, flexibility and functionality. The implants of these materials have low risks of inflammation and infection. Many customized orthopedic implants treat knee prosthetics, acetabular cups, spinal implants etc. 116

Inion CPS is an FDA approved biodegradable polymer made by trimethylene carbonate, L-lactide, D, L-lactide and polyglycolide. Used to fix craniofacial fractures and shows similar mechanical/degradable properties like titanium. Morphix is an FDA-approved shape memory biopolymeric material that exists for orthopedic usage as an anchor suture. This material is a bioresorbable polymer and helps to regenerate new tissues. 117 Even after a lot of improvements regarding fourth generation biomaterials, there are challenges/issues concerning clinical trials and human usage. Here, the FDA approved polymers/scaffold materials used in orthopedic applications-clinical/Human trials, are listed in Table 1.

Table 1 Clinical grade FDA approved implants/SMPs for orthopedic applications Note: SR; Self-reinforced, PGA; polyglycolic acid, PLLA; poly-l-lactic acid, PDLLA; poly-d-l-lactic acid, TMC; trimethylene carbonate, u-HA; unsintered hydroxyapatite, PDS; polydioxanone, PHBHV; Poly (3-hydroxybutyrate-co-3-hydroxyvalerate.
Sl. No FDA approved polymer products Polymers composition Expected applications Ref. No
1 Restore® Porcine small intestine submucosa (SIS) ECM patches for reinforcement of soft-tissue repair during rotator cuff surgeryRotator cuff repair 1
2 CuffPatch™
3 GraftJacket Human dermis
4 TissueMend soft Bovine Fetal dermis
5 Zimmer Collagen Porcine dermis
6 TissueMend® Fetal bovine skin
7 SINEFIX TM PEEK
8 REGENETEN™ Bovine Facilitates tendon like tissue regrowth associated with rotator cuff repair 2
9. Osteoplug™ PCL Trephination burr hole coverage 3
10 Osteomesh™ Cranifacial repair 4
11 Biofix® SR-PGA SR-PGA Polymeric Implants used as plates and screws for maxillofacial bone fixation 5
12 Biofix® SR-PLLA SR-PLLA
13 Resomer® LR708 PLLA + PDLLA
14 MacroPore®
15 Macrosorb®
16 Biosorb FX®
17 Resorb X®
18 PolyMax® RAPID PLLA + PGA
19 Rapidsorb®
20 Lactosorb®
21 Delta® PLLA, PGA and PDLA
22 Inion CPS® PLLA, PGA, varied proportion of TMC-
23 Inion CPS ® baby PLLA, PGA,
24 OsteotransMX PLLA, uHA
25 BIO-BRACETM Highly porous type 1 collagen + PLLA Tendan ligament repair 6
26 Altera® PEEK Designed to fix soft tissues 7
27 ExoShape® Soft tissue repair
28 Morphlx® Suture-anchor system, repairing worn tendons and ligaments
29 Carticel Uses autologous chondrocytes Repair of femoral condyle 8
30 OP-1 Implant Carboxymethyle cellulose and type 1 bone collagen Alternative to autograft for the long bone repair 9
31 InFUSE Bone Graft Type 1 collagen and rhBMP-2 along with excipients Spinal fusion for degenerative disc disease 10
32 DEXON PLLA High strength fibre used for orthopedicsutures 11
33 Bio-Anchor Orthopedic fixative devices
34 Meniscal Stinger
35 The clearfix Meniscal Dart
36 Dacron Ligament replacement
37 Pins PDS Fixative screws for small bone and 39osteochondrial fragments
38 Acufex PHBHV
39 SYNVIC, ORTHOVISC Viscous HA To releaf pain in joints of osteoarthritis patients
4.3

4.3 Applications of smart programmable shape memory polymers on soft tissue and hard tissue

Critical bone cartilage defects may arise from injuries, inherited defects, and tumor erasure, which are challenging in orthopedics. Bone tissue comprises both soft tissue and hard tissue. Allografts are associated with risk of infection, inflammation and limited osteointegration. It is difficult to match the grafts for soft bone defects. Poor contacts between the graft and surrounding tissue of the bone may increase the risk of non-integration. 105 Precise shaped scaffolds have limitations associated with shape fabrication process. Hence, injectable scaffolds form perfect in-situ solid scaffolds and accommodated within the bone defects. These injectable scaffold materials include hydrogels, cryogels, glass ceramics etc. However, injectable scaffold materials have poor mechanical strength and interconnectivity between the surrounding cells. 118 Therefore, novel porous bone scaffold materials are developed from self-fitting SMPs with compact shape and shape retrieval behaviors. The healing process of cartilage (soft bone) is tedious because of its dense structure without lymphatic connection. Hence, the growth factors, other cell types are limited to the site of defect.

SMPs provides a complete microstructure for chondrocyte adhesion, proliferation and fills the gaps in defects. RGD (arginylglycylaspartic acid) peptides coated hyaluronic acid cryogels are seeded with chondrocytes and injected in the defected area. The injected gel is compatible with the cells by shape memory effect. Immunohistochemistry studies revealed that seeded chondrocytes produce collagen type II and glycosaminoglycans within the cryogels. This study showed the interaction between the seeded cells and cryogel. This is due to the high porous connective network of hyaluronic acid. 119 In another example, micro-computed tomography scanning study reveals the establishment of in growth of bone with the peripheral regions of polyurethane/hydroxyapatite based SMP. Histological studies unveil the effective vascularization and remodeling of bone. 120

The larger fracture defects (hard bone tissue) are healed up easily compared to critical sized defects. Synthetic polymer-based scaffolds are used to design specific shapes of the defect. Injectable scaffolds are used to fix the complex size of the defect. For example, injectable hydrogels fill 3D defects related to hard tissue repairs. Smart polymers are molded to combat biofilm formation and reduce drug-resistant bacteria. PCL and hydroxyapatite shape memory foam loaded with morphogenic protein-2 (BMP-2) and fabricated with calcium alginate is an excellent material to repair mandibular bone defects. This porous scaffold displayed good shape memory behavior/recovery. In vitro cytotoxicity test (MTT test), CT-scan, and histomorphometry results reveal biocompatible behavior. 121 Another classical example is the nanocomposites of poly (D, L-lactide) and hydroxyapatite are operated by temperature responsive SMPs. Studies showed that they are good cytocompatibility and help in slow release of bone morphogenic protein-2 (stimulates cell differentiation) in mandibular bone defects in rabbit models. 122

4.4

4.4 Shape memory polymer-based programmable scaffolds as drug releasing systems

Shape memory polymers-based scaffolds have received tremendous attention for the application of active targeted drug delivery by non-invasive methods for the treatment of bone defects. The drug-eluting implants/scaffolds are facilitating the healing process in bone defects. The responsive type of SMPs materials scaffolds is in attention in many orthopedic applications. The healing of bone-tendon defects may take longer periods. To address this issue, engineered SMP scaffolds are loaded with drugs/stem cells to enhance healing and regeneration of cells. Many reports suggest the incorporation of drugs inside the solid implants/scaffold material leads to better osseointegration. The space between the solid materials is less compared to liquid and gas. A spacer material is mixed with the solid scaffolds so that drugs can be efficiently introduced inside. For example, ammonium hydrogen carbide (NH5CO3) is a spacer material for magnesium-based scaffold. Later the spacer is removed by sintering at high temperature. Similarly, sodium chloride in the polycaprolactone material (PCL) requires Mg as spacer. 123 The drugs like antibacterial materials are impregnated with implant matrix to act in situ mode. The use of mesoporous silica nanoparticles (MSNs), mesoporous hydroxyapatite (mHAP) and mesoporous calcium phosphates (mCaPs) were effectively used for the regeneration of bone tissues. 124 PEG modified manganese doped hollow MSNs (Mn-HMSNs) for rapid biodegradation and theragnostic functions under pH responsive condition. In addition to this, Si-o-Si bonds breaks with fast release of cargo drugs. This strategy is called metal ion doping.. 125 Similarly, mHAP provides porous surface just like bone with osteoconductive and osteoinductive properties. 126 Yu. Weilin et al. demonstrated strontium doped amorphous CaPs, have similar potential with respect to osteopontin synthesis and regeneration. The surface of these materials was tuned to increase surface parameters. 127 Another example is smart composites made by melatonin-loaded polycaprolactone (PCL) and sodium alginate hydrogels. Drug melatonin is (natural antioxidant) released in a controlled manner from the scaffold and effectively involved in tendon repair. 128 Hydrogels were loaded with aspirin and bone mesenchymal stem cells showed good osteogenesis in bone defects. Similarly, aldehyde-modified hyaluronic acid methacrylate (ADH-HAMA) and oxidized hyaluronic acid (OHA) are making more stable scaffold material in rat calvaria by increased recruitment of M2 macrophages. 129 Bio glass scaffolds developed using mesoporous bio glass/chitosan for the release of ursolic acid drug. The released drug increased the osteogenic differentiation. 130 Double layered with highly porous PLA based electro spun nanofibers as scaffolds were loaded with drugs such as phenytoin and sildenafil. The drugs were efficiently released and helps in bone tissue regeneration. The histopathological studies, cytotoxicity, cell adhesion and proliferation studies reveal the efficient release of drugs which helps in renewal of tissues in bone fractures. 131 Similarly, hydroxyapatite microspores (HHMs) with chitosan scaffolds were used to release recombinant human C-X-C motif chemokine ligand 13 (rhCXCL13) leads to recruitment of BMSCs, osteogenesis in bone defects. 132 Anti-inflammatory drugs such as pueranin loaded to zeolitic imidazole framework-8 (ZIF-8) demonstrated for excellent osteogenic differentiation and anti-inflammatory effects. 133 Mesoporous silica (MS)/PLGA was loaded with silk fibroin/carboxymethyl chitosan/sodium alginate (MP/SF/CMCS/SA) for the release of rhodamine at 1 % MP showed bone regeneration in both in vivo and in vitro conditions. 134 The layered double hydroxide-chitosan porous scaffolds were used for excellent osteogenic differentiation and bone regeneration within 12 weeks post-implantation in rats. 135 PCL/lignin nano-fibrous membranes were used as artificial periosteum in both in-vitro and in-vivo models. Here, lignin acts as an antibacterial agent to control both E. coli and S. aureus. 136 The above examples suggest the efficiency of SMPs based drug releasing materials.

5

5 Challenges for orthopedic shape memory polymeric implants/scaffolds

Many more advanced shape memory alloys/ceramic/polymers are used successfully in orthopedic implants due to similar biomechanical properties concerning physiology of bone. Novel shape memory alloys/metal composite materials have great potential to use as implants but need to address the issues related to non-biodegradability, toxicity effects. The discovery of biodegradable new polymers has challenges in its fabrication methods to enhance the osteo-biological properties. 137 Bone angiogenesis and bone formation are crucial for the bone reconstruction, healing and associated with complex processes like chemotaxis, adhesion, proliferation and differentiation of vascular endothelial progenitor cells. Hence, selected implant/scaffold polymers should induce osteogenic/angiogenic properties. Studies like toxicity, efficacy, biocompatibility, safety of use of the polymers/implants is crucial. Multipart bone fractures and post operative complications associated with microbial infections are still challenging in ortho clinics. The infections may be caused due to the formation of biofilms on the surface of implants, requiring secondary surgery. These revised surgeries are more complex and expensive associated with more pain and incapacity of the patients. The challenging part is identifying the source of implant failure due to infections. Because the treatments are biased by giving antibiotics/painkillers externally, it makes implants more efficacious and biocompatible. 138 Tissue engineering field is progressive, and the role of natural/synthetic scaffolds need to enhance to mimic the natural ECM required for osteogenesis. Further, detailed study on the interactions between immune cells and SMPs scaffold will pave the way for effective orthopedic regenerative therapy. Given this, the respective signaling pathways connected with osteo-genesis/conduction/integration need to be elucidated to better understand in vivo details.

Apart from the above technical studies, the process of regulatory approvals from the various bodies/organizations is needed for use of new polymers. Surface modification of hydrogel polymers forms a specific 3-dimensional network in the presence of water, prepared by both synthetic and biopolymers. Hydrogels are effectively used to repair cartilage defects. Future research should focus on developing a new combination of bio/synthetic polymers that aims to increase biodegradable rate, optimize functionalization/coating on the surface of scaffolds for enhancing better attachment of cells, non-toxicity, etc. Also need to focus on the increase of biomechanical properties of polymers. To address all the above issues, thorough interdisciplinary research is required in collaboration of material science and clinicians.

Moreover, many shape memory implants/scaffold materials need to be tested with invitro and many animal models. Even though the studies may show positive results with respect to the osteo-biological behavior under in vitro conditions/animal experiments, it is prime important to focus with respect to the human clinical trials. The advancement of the study of interactions of polymers with bone microenvironment leads to better understanding of real clinical problems. Hence, more focus should orient towards clinical trials are warranted.

6

6 Future prospectus

Despite continuous evolution of smart metal/biopolymeric/nano materials, limited, clinical approved materials are present. In many situations like severe fractures, joint breakdowns, and osteopathological conditions different metal devices/prosthesis were used, still needed in the treatments and not replaced. Hence, even first-generation shape memory alloys to fourth generation polymers have their own scope, advantages and disadvantages. In recent studies, use of artificial intelligence (AI) based bone scaffold design is more prominent, reduces errors and minimizes the time. With the advancements of biomedical data, significantly reduced the costs and increased the efficiency of the production of customized scaffolds. AI has revolutionized with the diagnosis of bone defects/fractures. Several risk prediction tools like; Fracture Risk Assessment Tool (FRAX) and Garvan Fracture Calculator and QFracture score were used. 139 AI helping the researchers in material selection, construction of complex scaffold geometries, interaction studies of bone scaffolds. With the use of suitable machine learning models, helps to study mechanical and flow properties of the scaffold material and reduces the cost of invivo and invitro studies. 140 Whereas there is much opportunity to improve the biomechanical properties. AI reduces the burdon of in vivo experiments with high precise outputs. In addition, Nano particles have versatile advantages because of their nanostructures, are used as drug delivery molecules in case of bone cancer and facilitates the downregulation of specific cancer-causing genes. For example, titanium surfaces coated with selenium clusters can potentially inhibit bone malignancy. 116 The cost required for the tissue engineering market is quite high. The technology must address in vitro/animal studies related to scaffold fabrication, tunability in its physicochemical properties etc. Several challenges remain in case of stimuli responsive SMPs. For example, thermos responsive SMPs need to program precise transition temperature according to polymer composition. Because different physiological temperatures are registered at different pathological/infection/inflammation conditions. Design of custom based implants for individual patients with good biomechanical properties is an important step for the future therapeutics. Construction of 3D printed SMPs are promising technology, need to address various clinical challenges related to bone tissue regeneration. It necessitates a thorough study before selection for custom made implants. Self-fitting SMPs. 5D and 6D printing technology will synthesize specific curved axes of bone in multiple dimensions, hence the need to emphasize the design of multiple intelligence shape memory polymers with multidimensional technology. 117

7

7 Conclusions

Bone surgery is complex and associated with many challenges for clinicians and material science engineers. Metal/nonmetal polymer/biomaterials have been used and associated with bone surgeries. Metal implants such as titanium/cobalt/magnesium alloys have excellent mechanical properties. However, limited osteobiological properties are exhibited by metal alloys. On the other side, next generation smart SMPs materials have excellent biomechanical properties and osteobiological properties. Since, the polymeric materials are prepared in the form of composites, functionalized with nanomaterials, biomolecules etc to create the exact microenvironment just like in vivo. AI based personal treatments can be possible by analyzing patients details, design of scaffolds. Overall the evolution from traditional SMA to SMPs is opening a new avenue in the field of bone tissue engineering.

Reviewer declaration statement

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical statement

Not applicable.

Guardian statement

Not applicable.

Funding statement

Not funded by any ageencies

Credit author statement

Anupama C: Proof of concept, writing and editing, validation

Sriharsha Kumar: Writing the draft, data collection, curation

Abhijith Shettar: Writing, validation

Arun Y C: Validation, data collection

References

  1. , , . Challenges of bone tissue engineering in orthopaedic patients. World J Orthoped. 2017;8(2):87-98.
    [Google Scholar]
  2. , , , , . Advances in bone tissue engineering: a fundamental review. J Biosci. 2021;46
    [Google Scholar]
  3. , , , , , , . Mechanical basis of bone strength: influence of bone material, bone structure and muscle action. J Musculoskelet Neuronal Interact. 2017;17(3):114-139.
    [Google Scholar]
  4. , , , et al . A comprehensive review on metallic implant biomaterials and their subtractive manufacturing. Int J Adv Manuf Technol. 2022;120(3-4):1473-1530.
    [Google Scholar]
  5. , , , . A comprehensive review of biodegradable synthetic polymer-ceramic composites and their manufacture for biomedical applications. Bioact Mater. 2019;4(1):22-36.
    [Google Scholar]
  6. , , , et al . Biomaterials as implants in the orthopedic field for regenerative medicine: metal versus synthetic polymers. . 2023;15(12):2601.
    [Google Scholar]
  7. , , . Solvent responsive shape memory Polymers- evolution, current status, and future outlook. Macromol Chem Phys. 2021;222(19)
    [Google Scholar]
  8. , , , , . Bioperspectives for shape-memory polymers as shape programmable, active materials. Biomacromolecules. 2019;20(10):3627-3640.
    [Google Scholar]
  9. , , , , . Recent advances in hydroxyapatite-based biocomposites for bone tissue regeneration in orthopedics. Int J Mol Sci. 2022;23(17)
    [Google Scholar]
  10. , , , et al . Strategies to improve bioactive and antibacterial properties of polyetheretherketone (PEEK) for use as orthopedic implants. Mater Today Bio. 2022;16
    [Google Scholar]
  11. , , , , . Cobalt Based Alloy: A Better Choice Biomaterial for Hip Implants. 2016;vol. 30:50-55.
    [Google Scholar]
  12. , , , et al . Corrosion behavior of nickel–titanium continuous-casted alloys. Metals. 2024;14(1)
    [Google Scholar]
  13. , , , . Atomic layer deposition of aTiO2 layer on nitinol and its corrosion resistance in a simulated body fluid. Metals. 2021;11(659)
    [Google Scholar]
  14. , , , et al . Investigating antibacterial activity of copper-silver-cerium alloys. Metals. 2024;14(12)
    [Google Scholar]
  15. , . Studies in bone growth: triple calcium phosphate as a stimulus to osteogenesis. Ann Surg. 1920;71(1):32-39.
    [Google Scholar]
  16. , , , , . Bioactive glass in cavitary bone defects: a comparative experimental study in rabbits. Acta Ortopédica Bras. 2015;23(4):202-207.
    [Google Scholar]
  17. , , , et al . Current progress in bioactive ceramic scaffolds for bone repair and regeneration. Int J Mol Sci. 2014;15(3):4714-4732.
    [Google Scholar]
  18. , , , et al . Cementless ceramic-on-ceramic total hip replacement in children and adolescents. Children. 2021;8(10)
    [Google Scholar]
  19. , , , et al . Thermosensitive hydrogel loaded with concentrated growth factors promote bone repair in segmental bone defects. Front Bioeng Biotechnol. 2022;10
    [Google Scholar]
  20. , , , . Advanced polymer-based composites and structures for biomedical applications. Eur Polym J. 2021;149
    [Google Scholar]
  21. , , , et al . 3D printing of bone and cartilage with polymer materials. Front Pharmacol. 2022;13
    [Google Scholar]
  22. , , . Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng B Rev. 2013;19(6):485-502.
    [Google Scholar]
  23. , , , , , . VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J Bone Miner Res : Off J Am Soc Bone Miner Res. 2006;21(5):735-744.
    [Google Scholar]
  24. , , , , . Smart scaffolds in bone tissue engineering: a systematic review of literature. World J Stem Cell. 2015;7(3):657-668.
    [Google Scholar]
  25. , , , . Natural and synthetic polymers for biomedical and environmental applications. Polymers. 2024;16(8)
    [Google Scholar]
  26. , , , , , , . Shape-memory polymers hallmarks and their biomedical applications in the form of nanofibers. Int J Mol Sci. 2022;23(3)
    [Google Scholar]
  27. , , , , , , . Impact of the magnetic field on 3T3-E1 preosteoblasts inside SMART silk fibroin-based scaffolds decorated with magnetic nanoparticles, materials science & engineering. C. Mater Biol Applic. 2020;110
    [Google Scholar]
  28. , , . Light-responsive inorganic biomaterials for biomedical applications. Adv Sci (Weinheim, Baden-Wurttemberg, Germany). 2020;7(17)
    [Google Scholar]
  29. , , , . Poly(ε-Caprolactone)/Poly(Glycerol sebacate) composite nanofibers incorporating hydroxyapatite nanoparticles and simvastatin for bone tissue regeneration and drug delivery applications. Polymers. 2020;12(11)
    [Google Scholar]
  30. , , , , , . Different modification methods of poly methyl methacrylate (PMMA) bone cement for orthopedic surgery applications. Arch Bone Joint Surg. 2023;11(8):485-492.
    [Google Scholar]
  31. , , , et al . The role of Poly(Methyl methacrylate) in management of bone loss and infection in revision total knee arthroplasty: a review. J Funct Biomater. 2020;11(2)
    [Google Scholar]
  32. , , , , . Advancements in soft-tissue prosthetics part B: the chemistry of imitating life. Front Bioeng Biotechnol. 2020;8:147.
    [Google Scholar]
  33. , , . Silicon, a possible link between environmental exposure and autoimmune diseases: the case of rheumatoid arthritis. Arthritis. 2012;2012
    [Google Scholar]
  34. , , , , . Silicone implant sandwiched between intact nasal bones with fractured nasal bone segments. Archives of craniofacial surgery. 2017;18(1):59-61.
    [Google Scholar]
  35. , . Carbon nanotubes and their polymeric composites: the applications in tissue engineering. Biomanuf Rev. 2020;5(1):3.
    [Google Scholar]
  36. , , , et al . Towards a new generation of non-cytotoxic shape memory thermoplastic polyurethanes for biomedical applications. Mater Today Commun. 2022;33
    [Google Scholar]
  37. , , , , , . Effect of carbon fiber type on monotonic and fatigue properties of orthopedic grade PEEK. J Mech Behav Biomed Mater. 2019;90:484-492.
    [Google Scholar]
  38. , , , et al . Fabrication of core–shell Ag@Pda@Hap Nanoparticles with the Ability for Controlled Release of Ag+ and Superior Hemocompatibility. 2017;vol. 7:29368-29377.
    [Google Scholar]
  39. , , , et al . Bacteria-triggered pH-Responsive osteopotentiating coating on 3D-Printed polyetheretherketone scaffolds for infective bone defect repair. Ind Eng Chem Res. 2020;59(26):12123-12135.
    [Google Scholar]
  40. , , , et al . Long-term induction of endogenous BMPs growth factor from antibacterial dual network hydrogels for fast large bone defect repair. J Colloid Interface Sci. 2022;607:1500-1515.
    [Google Scholar]
  41. , , , et al . Surface-modified polypyrrole-coated PLCL and PLGA nerve guide conduits fabricated by 3D printing and electrospinning. Biomacromolecules. 2022;23(11):4532-4546.
    [Google Scholar]
  42. , , , , , . Shape memory polymers as smart materials. Review. 2022;14(17):3511.
    [Google Scholar]
  43. , , , , . Polymeric biomaterials for scaffold-based bone regenerative engineering. Regener Eng Translat Med. 2019;5(2):128-154.
    [Google Scholar]
  44. , , , , , , . Electrospun biomimetic fibrous scaffold from shape memory polymer of PDLLA-co-TMC for bone tissue engineering. ACS Appl Mater Interfaces. 2014;6(4):2611-2621.
    [Google Scholar]
  45. , , , et al . The clinical use of osteobiologic and metallic biomaterials in orthopedic surgery: the present and the future. Materials. 2023;16(10)
    [Google Scholar]
  46. , . Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(suppl ment_3)
    [Google Scholar]
  47. , . Chemical and biochemical basis of cell-bone matrix interaction in health and disease. Curr Chem Biol. 2009;3(2):189-196.
    [Google Scholar]
  48. , , , . A Brief Review of Bone Cell Function and Importance. 2023;vol. 12
    [Google Scholar]
  49. , , , , . Piezoelectric smart biomaterials for bone and cartilage tissue engineering. Inflamm Regen. 2018;38(1):2.
    [Google Scholar]
  50. , , , et al . Bone physiological microenvironment and healing mechanism: basis for future bone-tissue engineering scaffolds. Bioact Mater. 2021;6(11):4110-4140.
    [Google Scholar]
  51. , , , et al . 3D-printed manganese dioxide incorporated scaffold promotes osteogenic-angiogenic coupling for refractory bone defect by remodeling osteo-regenerative microenvironment. Bioact Mater. 2025;44:354-370.
    [Google Scholar]
  52. , , , et al . Hybrid fracture fixation systems developed for orthopaedic applications: a general review. J Orthopaed Transl. 2019;16:1-13.
    [Google Scholar]
  53. , , , et al . The investigation of bone fracture healing under intramembranous and endochondral ossification. Bone Rep. 2021;14
    [Google Scholar]
  54. , , , , . The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr Opin Hematol. 2015;22(4):273-278.
    [Google Scholar]
  55. , , , et al . Programmed release of hydrogel microspheres via regulating the immune microenvironment to promotes bone repair. Mater Today Adv. 2023;18
    [Google Scholar]
  56. , , , . Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res Part C, Embryo Today : Reviews. 2013;99(3):203-222.
    [Google Scholar]
  57. , , , . Osseointegration and current interpretations of the bone-implant interface. Acta Biomater. 2019;84:1-15.
    [Google Scholar]
  58. , , , , , . Materials and manufacturing techniques for polymeric and ceramic scaffolds used in implant dentistry. . 2021;5(3):78.
    [Google Scholar]
  59. , , , , . Regulation of the mesenchymal stem cell fate by interleukin-17: implications in osteogenic differentiation. World J Stem Cell. 2021;13(11):1696-1713.
    [Google Scholar]
  60. , , , et al . Biopolymer-based composites for tissue engineering applications: a basis for future opportunities. Compos B Eng. 2023;258
    [Google Scholar]
  61. , , , et al . Biomaterials as implants in the orthopedic field for regenerative medicine: metal versus synthetic polymers. Polymers. 2023;15(12)
    [Google Scholar]
  62. , , , . Scaffold design for bone regeneration. J Nanosci Nanotechnol. 2014;14(1):15-56.
    [Google Scholar]
  63. , , , , , , . Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces. Acta Biomater. 2013;9(5):6663-6674.
    [Google Scholar]
  64. , , , . Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther. 2007;9(Suppl 1):S6.
    [Google Scholar]
  65. , , , et al . Advanced smart biomaterials and constructs for hard tissue engineering and regeneration. Bone Res. 2018;6(1):31.
    [Google Scholar]
  66. , , , , . Biodegradable polymers in bone tissue engineering. Materials. 2009 Jul 24;2(3):833-856.
    [Google Scholar]
  67. , . Recent advances and perspective of nanotechnology-based implants for orthopedic applications. Front Bioeng Biotechnol. 2022;10
    [Google Scholar]
  68. , , , , . The applicability of nanostructured materials in regenerating soft and bone tissue in the oral cavity. Review. 2024;9(6):348.
    [Google Scholar]
  69. , , , , . Oxygen and nutrient delivery in tissue engineering: approaches to graft vascularization. J Tissue Eng Regen Med. 2019;13(10):1815-1829.
    [Google Scholar]
  70. , , , , . Biomaterials and host versus graft response: a short review. Bosn J Basic Med Sci. 2016;16(2):82-90.
    [Google Scholar]
  71. , , , , , , . A multifunctional porous scaffold with capacities of minimally invasive implantation, self-fitting and drug delivery. Mater Today Chem. 2016;1–2:52-62.
    [Google Scholar]
  72. , , , et al . Characterization and optimization of actuating poly(ethylene glycol) diacrylate/acrylic acid hydrogels as artificial muscles. Polymer. 2017;117:331-341.
    [Google Scholar]
  73. , , , . Fabrication of scaffolds for bone-tissue regeneration. . 2019;12(4):568.
    [Google Scholar]
  74. , , , et al . A mechanical analysis of chemically stimulated linear shape memory polymer actuation. . 2021;14(3):481.
    [Google Scholar]
  75. , , , , , , . Osteogenic capacity of human adipose-derived stem cells is preserved following triggering of shape memory scaffolds, tissue engineering. Part A. 2016;22(15-16):1026-1035.
    [Google Scholar]
  76. , , , , . Applications of shape memory polymers in kinetic. Buildings. 2018;1
    [Google Scholar]
  77. , , , , . Body temperature-responsive two-way and moisture-responsive one-way Shape Memory Behaviors of Poly(Ethylene Glycol)-based Networks. 2017;vol. 8:3833-3840.
    [Google Scholar]
  78. , , , , , . Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration. Bone Res. 2022;10(1):17.
    [Google Scholar]
  79. , , , et al . Self-assembled peptide and protein nanostructures for anti-cancer therapy: targeted delivery, stimuli-responsive devices and immunotherapy. Nano Today. 2021;38
    [Google Scholar]
  80. , , , et al . A dual-functional implant with an enzyme-responsive effect for bacterial infection therapy and tissue regeneration. Biomater Sci. 2020;8(7):1840-1854.
    [Google Scholar]
  81. , , , , . A review of shape memory polymers based on the intrinsic structures of their responsive switches. RSC Adv. 2021;11(46):28838-28850.
    [Google Scholar]
  82. , , , , , . Residual stress development and thermo-elasto-plastic distortion in brake discs. Tribol Int. 2023;190
    [Google Scholar]
  83. , , , . Development of new metallic alloys for biomedical applications. Acta Biomater. 2012;8(11):3888-3903.
    [Google Scholar]
  84. , , . Tuning biodegradability, bone-bonding capacity, and wear resistance of zinc-30% magnesium intermetallic alloy for use in load-bearing bone applications. Sci Rep. 2024;14(1):2425.
    [Google Scholar]
  85. , , , , , . Low-hysteresis shape memory alloy scale-up: DSC, XRD and microstructure analysis on heat-treated vacuum induction melted ni-ti-cu-pd. Alloys. 2021;11(9):1387.
    [Google Scholar]
  86. , , , et al . Metal implant removal: benefits and drawbacks – a patient survey. BMC Surg. 2015;15(1):96.
    [Google Scholar]
  87. , . Research and development of metals for medical devices based on clinical needs. Sci Technol Adv Mater. 2012;13(6)
    [Google Scholar]
  88. , , , , , . Improving biocompatibility for next generation of metallic implants. Prog Mater Sci. 2023;133
    [Google Scholar]
  89. , , , , , , . Total hip arthroplasty: past, present, and future. What has been achieved? Hip & pelvis. 2019;31(4):179-189.
    [Google Scholar]
  90. , , , et al . Influence of porosity on osteogenesis, bone growth and osteointegration in trabecular tantalum scaffolds fabricated by additive manufacturing. Front Bioeng Biotechnol. 2023;11
    [Google Scholar]
  91. , , , , , , . Porous bone tissue scaffold concept based on shape memory PLA/Fe3O4. Compos Sci Technol. 2021;203
    [Google Scholar]
  92. , , , , . Sustainable materials and technologies for biomedical applications. Adv Mater Sci Eng. 2023;2023(1)
    [Google Scholar]
  93. , , , , , . Biomimetic porous scaffolds for bone tissue engineering. Mater Sci Eng R Rep. 2014;80:1-36.
    [Google Scholar]
  94. , , , et al . Preparation of multigradient hydroxyapatite scaffolds and evaluation of their osteoinduction properties. Regen Biomater. 2022;9
    [Google Scholar]
  95. , , , , . Customized additive manufacturing in bone scaffolds-the gateway to precise bone defect treatment. Research. 2023;6:239.
    [Google Scholar]
  96. , , , , , . Collagen type I biomaterials as scaffolds for bone tissue engineering. Polymers. 2021;13(4)
    [Google Scholar]
  97. , , , . Structural arrangements at the interface between plasma sprayed calcium phosphates and bone. Biomaterials. 1994;15(7):543-550.
    [Google Scholar]
  98. , , , , , , . Dairy-inspired coatings for bone implants from whey protein isolate-derived self-assembled fibrils. Int J Mol Sci. 2020;21(15)
    [Google Scholar]
  99. , , , , , , . Healos and bone marrow aspirate used for lumbar spine fusion: a case controlled study comparing healos with autograft. Spine. 2006;31(18):E636-E640.
    [Google Scholar]
  100. , , , , . Self-healable conductive polyurethane with the body temperature‐responsive shape memory for bone tissue engineering. Chem Eng J. 2021;411
    [Google Scholar]
  101. , , . A materials perspective on the design of damage-resilient bone implants through additive/advanced manufacturing. JOM. 2020;72(3):1195-1210.
    [Google Scholar]
  102. , , , , . Two-way shape memory behavior of styrene-based bilayer shape memory polymer plate. Polym Adv Technol. 2023;34(1):252-260.
    [Google Scholar]
  103. , , , et al . Enhanced biocompatibility of polyurethane-type shape memory polymers modified by plasma immersion ion implantation treatment and collagen coating: an in vivo study. Mater Sci Eng C. 2019;99:863-874.
    [Google Scholar]
  104. , , . Smart scaffolds: shape memory polymers (SMPs) in tissue engineering. J Mater Chem B. 2021;9(21):4287-4297.
    [Google Scholar]
  105. , , , et al . Self-fitting shape memory polymer foam inducing bone regeneration: a rabbit femoral defect study. Biochim Biophys Acta Gen Subj. 2018;1862(4):936-945.
    [Google Scholar]
  106. , , , et al . Concentrated growth factors (CGF) induce osteogenic differentiation in human bone marrow stem cells. Biology. 2020;9(11)
    [Google Scholar]
  107. , , , et al . 3D-printed porous zinc scaffold combined with bioactive serum exosomes promotes bone defect repair in rabbit radius. Aging. 2024;16(11):9625-9648.
    [Google Scholar]
  108. , , , et al . Evaluation of osteogenesis and angiogenesis of icariin loaded on micro/nano hybrid structured hydroxyapatite granules as a local drug delivery system for femoral defect repair. J Mater Chem B. 2015;3(24):4871-4883.
    [Google Scholar]
  109. , , , , , , . Smart hydrogels for bone reconstruction via modulating the microenvironment. Research. 2023;6:89.
    [Google Scholar]
  110. , , , et al . Cerium oxide nanoparticles promote osteoplastic precursor differentiation by activating the wnt pathway. Biol Trace Elem Res. 2023;201(2):865-873.
    [Google Scholar]
  111. , , , et al . Capturing cerium ions via hydrogel microspheres promotes vascularization for bone regeneration. Mater Today Bio. 2024;25
    [Google Scholar]
  112. , , , et al . Fabrication of biocompatible porous scaffolds based on hydroxyapatite/collagen/chitosan composite for restoration of defected maxillofacial mandible bone. Prog Biomater. 2019;8(3):137-154.
    [Google Scholar]
  113. , , , , . Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol. 2014;12(4):207-218.
    [Google Scholar]
  114. , , , . Tuning the biomimetic behavior of scaffolds for regenerative medicine through surface modifications. J Tissue Eng Regen Med. 2019;13(8):1275-1293.
    [Google Scholar]
  115. , , , , , , . A poly(ethylene glycol) three-dimensional bone marrow hydrogel. Biomaterials. 2022;280
    [Google Scholar]
  116. , , . Significant advancements of 4D printing in the field of orthopaedics. Journal of clinical orthopaedics and trauma. 2020;11(Suppl 4):S485-s490.
    [Google Scholar]
  117. , , , et al . Shape memory polymeric materials for biomedical applications: an update. . 2023;7(1):24.
    [Google Scholar]
  118. , , , . Design challenges in polymeric scaffolds for tissue engineering. Front Bioeng Biotechnol. 2021;9
    [Google Scholar]
  119. , , , et al . A mechanical analysis of chemically stimulated linear shape memory polymer actuation. Materials 2021
    [Google Scholar]
  120. , , , , , , . MicroCT analysis of hydroxyapatite bone repair scaffolds created via three-dimensional printing for evaluating the effects of scaffold architecture on bone ingrowth. . 2008;85A(2):371-377.
    [Google Scholar]
  121. , , , , , , . Porous 3D scaffolds enhance MSC vitality and reduce osteoclast activity. Molecules. 2021;26(20)
    [Google Scholar]
  122. , , , et al . Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Biomacromolecules. 2014;15(3):1019-1030.
    [Google Scholar]
  123. , , , . Drug-loaded biomaterials for orthopedic applications: a review. J Contr Release. 2022;344:113-133.
    [Google Scholar]
  124. , , , et al . Smart cargo delivery system based on mesoporous nanoparticles for bone disease diagnosis and treatment. Adv Sci (Weinheim, Baden-Wurttemberg, Germany). 2021;8(12)
    [Google Scholar]
  125. , , , et al . Strontium-doped amorphous calcium phosphate porous microspheres synthesized through a microwave-hydrothermal method using fructose 1,6-Bisphosphate as an organic phosphorus source: application in drug delivery and enhanced bone regeneration. ACS Appl Mater Interfaces. 2017;9(4):3306-3317.
    [Google Scholar]
  126. , , . Nanoscale hydroxyapatite particles for Bone Tissue Engineering. . 2011;7(7):2769-2781.
    [Google Scholar]
  127. , , , , , . Biomolecule-assisted green synthesis of nanostructured calcium phosphates and their biomedical applications. Chem Soc Rev. 2019;48(10):2698-2737.
    [Google Scholar]
  128. , , , et al . Biomimetic multilayer polycaprolactone/sodium alginate hydrogel scaffolds loaded with melatonin facilitate tendon regeneration. Carbohydr Polym. 2022;277
    [Google Scholar]
  129. , , , et al . Injectable hyaluronate-based hydrogel with a dynamic/covalent dual-crosslinked architecture for bone tissue engineering: enhancing osteogenesis and immune regulation. Int J Biol Macromol. 2024;282(Pt 5)
    [Google Scholar]
  130. , , , et al . Ursolic acid loaded-mesoporous bioglass/chitosan porous scaffolds as drug delivery system for bone regeneration. Nanomed Nanotechnol Biol Med. 2019;18:336-346.
    [Google Scholar]
  131. , , , . Phenytoin/Sildenafil loaded poly(lactic acid) bilayer nanofibrous scaffolds for efficient orthopedics regeneration. Int J Biol Macromol. 2019;136:154-164.
    [Google Scholar]
  132. , , , et al . Hollow hydroxyapatite microspheres loaded with rhCXCL13 to recruit BMSC for osteogenesis and synergetic angiogenesis to promote bone regeneration in bone defects. Int J Nanomed. 2023;18:3509-3534.
    [Google Scholar]
  133. , , , et al . Tannic acid and quaternized chitosan mediated puerarin-loaded octacalcium phosphate/sodium alginate scaffold for bone tissue engineering. Int J Biol Macromol. 2024;271(Pt 2)
    [Google Scholar]
  134. , , , et al . Preparation and osteogenesis of a multiple crosslinking silk fibroin/carboxymethyl chitosan/sodium alginate composite scaffold loading with mesoporous silica/poly (lactic acid-glycolic acid) microspheres. J Biomater Appl. 2025;39(6):578-591.
    [Google Scholar]
  135. , , , , , , . MgAl layered double hydroxide/chitosan porous scaffolds loaded with PFTα to promote bone regeneration. Nanoscale. 2017;9(20):6765-6776.
    [Google Scholar]
  136. , , , et al . Electrospun lignin-loaded artificial periosteum for bone regeneration and elimination of bacteria. Int J Biol Macromol. 2024;282(Pt 5)
    [Google Scholar]
  137. , , , et al . Fabrication of biodegradable and biocompatible functional polymers for anti-infection and augmenting wound repair. Polymers 2023
    [Google Scholar]
  138. , , , . Effect of antibiotics on implant failure and postoperative infection. Evid Base Dent. 2014;15(2):58.
    [Google Scholar]
  139. , , , , , . Application of artificial intelligence at all stages of bone tissue engineering. Biomedicines. 2023;12(1)
    [Google Scholar]
  140. , , , . Computational modelling and simulation of scaffolds for Bone Tissue Engineering. . 2024;12(4):74.
    [Google Scholar]

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