
==== Front
Drug Deliv
Drug Deliv
Drug Delivery
1071-7544
1521-0464
Taylor & Francis

39239763
10.1080/10717544.2024.2391001
2391001
Version of Record
Review Article
Review Article
Bone scaffolds-based localized drugs delivery for osteosarcoma: current status and future perspective
W. Liang et al.
Liang Wenqing a*
Long Hengguo a*
Zhang Hongwei a
Bai Juqin a
Jiang Bo b
Wang Jiangwei c
Fu Lifeng d
Ming Wenyi a
Zhao Jiayi a
Zeng Bin a
a Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
b Rehabilitation Department, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
c Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
d Department of Orthopedics, Shaoxing City Keqiao District Hospital of Traditional Chinese Medicine, Shaoxing, China
* These authors contributed equally to this work.

CONTACT Bin Zeng zb8280@163.com
Jiayi Zhao zjy2038689@sina.com Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai district, Zhoushan, Zhejiang Province 316000, China
6 9 2024
2024
6 9 2024
31 1 239100129 5 2023
1 8 2024
6 8 2024
KnowledgeWorks Global Ltd.5 9 2024
published online in a building issue5 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

A common malignant bone neoplasm in teenagers is Osteosarcoma. Chemotherapy, surgical therapy, and radiation therapy together comprise the usual clinical course of treatment for Osteosarcoma. While Osteosarcoma and other bone tumors are typically treated surgically, however, surgical resection frequently fails to completely eradicate tumors, and in turn becomes the primary reason for postoperative recurrence and metastasis, ultimately leading to a high rate of mortality. Patients still require radiation and/or chemotherapy after surgery to stop the spread of the tumor and its metastases, and both treatments have an adverse influence on the body’s organ systems. In the postoperative management of osteosarcoma, bone scaffolds can load cargos (growth factors or drugs) and function as drug delivery systems (DDSs). This review describes the different kinds of bone scaffolds that are currently available and highlights key studies that use scaffolds as DDSs for the treatment of osteosarcomas. The discussion also includes difficulties and perspectives regarding the use of scaffold-based DDSs. The study may serve as a source for outlining efficient and secure postoperative osteosarcoma treatment plans.

Keywords

Osteosarcoma
localized bone scaffolds
drug delivery systems
natural polymers
synthetic polymers
Public Technology Applied Research Projects of Zhejiang Province LGF22H060023 Medical and Health Research Project of Zhejiang Province 10.13039/501100017531 2022KY433 2021KY1164 Traditional Chinese Medicine Science and Technology Projects of Zhejiang Province 2022ZB382 2022ZB381 2023ZL765 Research Fund Projects of The Affiliated Hospital of Zhejiang Chinese Medicine University 2021FSYYZY45 This work was supported by Public Technology Applied Research Projects of Zhejiang Province (LGF22H060023 to WQL), Medical and Health Research Project of Zhejiang Province (2022KY433 to WQL, 2021KY1164 to LFF), Traditional Chinese Medicine Science and Technology Projects of Zhejiang Province (2022ZB382 to WQL, 2022ZB381 to JYZ, 2023ZL765 to WYM), Research Fund Projects of The Affiliated Hospital of Zhejiang Chinese Medicine University (2021FSYYZY45 to WQL).
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pmc1. Introduction

Osteosarcoma, which is characterized by osteolytic bone degradation and high rates of disability, is the most prevalent primary bone malignant tumor among children and adolescents (Moore & Luu, 2014). The annual reported incidence of osteosarcoma in children is approximately 4.4 cases per million (Esiashvili et al., 2008; Mirabello et al., 2009). Mortality rates have decreased predominantly as a result of the introduction of multiagent chemotherapy, whereas the incidence of osteosarcoma has remained relatively stable over the past 40–50 years (Ward et al., 2014). Osteosarcomas are frequently observed in the metaphysis of long bones, especially around the knee in the distal femur or proximal tibia. The majority of osteosarcoma cases occur in male adolescents, as is the case with Ewing sarcoma. Metastatic disease is present in up to 25% of patients upon diagnosis, with lung metastases being the most prevalent site (Eaton et al., 2021). Patients with osteosarcoma have a 5-year survival rate of ∼60% (Anderson, 2016). Unfortunately, over the past 40 years, advances in OS treatment have rather reached a plateau (Ballatori & Hinds, 2016).

2. Current approaches and limitations of osteosarcoma treatment

Prior to the last few decades, the treatment of osteosarcomas entailed invasive surgical procedures, which comprised inevitable disadvantages including the risk of significant psycho-mental health effects and frequent recurrences (Jaffe, 1972). Clinical surgery is often the first line of treatment against bone cancer since it is capable of removing the majority of solid tumors. Large-sized bone defects and spontaneous healing challenges are, nevertheless, the consequence of the limited regenerative capabilities of bone. Clinical treatments for this issue include both artificial replacements (implants) and biological grafts (allografts, autografts, and xenografts) (Bumgardner et al., 2007; Gerrand et al., 2016). However, there are a number of limitations to these scaffolds, such as the potential for infections, difficulties in identifying an appropriate donor, and impaired immune response. Besides this, contemporary therapeutic approaches involve the conservative administration of chemotherapy treatments both prior to and following surgery. The primary objective is to reduce the tumor mass prior to cancer resection, and any remaining tumor cells are subsequently eliminated (Holzapfel et al., 2011; Isakoff et al., 2015). Additional clinical approaches include chemotherapy, radiotherapy, and targeted cancer treatments when tumors have progressed to more advanced stages, metastasized to other body regions, or are unresectable (located in areas where surgery is challenging or carries a high risk) (Gerrand et al., 2016). Chemotherapeutics and targeted cancer treatments, including docetaxel (DTX), paclitaxel (PTX), daunorubicin, doxorubicin (DOX), and fluorouracil (5-FU), are administered in high systemic doses via these techniques (Makatsoris & Kalofonos, 2009). However, these substances are frequently associated with possible adverse effects including kidney toxicity (cisplatin) (Hanigan & Devarajan, 2003), myocardial and cardiac toxicity (DOX) (Takemura & Fujiwara, 2007; Volkova & Russell, 2011; Velasco & Bruna, 2015), and neurotoxicity (PTX) (Palumbo et al., 2013). Intravenous administration of anticancer drugs is restricted due to factors including low treatment efficacy, the necessity for hospitalization, frequent injection, and high cost as shown in Figure 1 (Lammers, 2010). The therapeutic window of anticancer drugs can be expanded with the use of localized DDS, which allows for the administration of lower doses while retaining effective intracellular concentrations (Kalimuthu et al., 2018). In addition, as mentioned earlier, the removal of osteosarcoma leaves behind substantial bone defects, and the regenerative healing of these flaws is a difficult surgical problem that can have negative effects on healthy tissues. Therefore, considerable interest has been devoted in developing new therapeutic strategies for the design and engineering of bone substitutes (Probst et al., 2010).

Figure 1. Illustration of the major drawbacks of conventional osteosarcoma treatment strategies.

3. Localized and sustain drug release therapeutic approach

In recent years, significant progress has been achieved in the field of drug delivery systems, giving rise to the concept of targeted drug delivery or localized controlled release. This innovation has provided solutions to various unresolved challenges; rather than considering the specific type of cancer, its primary objective is to eliminate cancerous cells while preserving healthy tissues (Gu et al., 2013; Mehrafzoon et al., 2018). When employing conventional drug delivery methods for the treatment of bone disease, a substantial dosage is necessary because blood flow through bone tissue is relatively insufficient in comparison to that of soft tissues (Foroughi et al., 2016). Consequently, it is evident that healthy organs would suffer severe consequences from the direct injection of extremely high doses of chemotherapy drugs into the bloodstream (Ansari et al., 2018). However, sustained release over a long period is expected to maintain the therapeutic window (Paolini et al., 2019). The development of novel, innovative treatment options for bone tumors has been improved by the advancement of nanotechnology. It is important to emphasize that the therapeutic efficacy of NPs consists of a reduction in side effects as well as a selective accumulation in the disease area for an extended period with great controllability (Liu et al., 2016). Because of their sustaifigurened drug release, extended-release NPs are appealing therapeutic possibilities for the long-term treatment of complex chronic disorders such as cancer (Owen & Rannard, 2015; Prosperi et al., 2017). Reduced fluctuations in drug levels are one of the benefits of these NPs that contribute to enhanced patient compliance, more effective drug life-cycle management, and prolonged symptom relief (Hoffman, 1998). Multiple dosages are common in cancer treatment, and this is a major contributor to the challenges that patients have with complying with their treatment plan (Kumari et al., 2010; Danhier et al., 2012). Patients often struggle with implementation and treatment perseverance while getting started in a new treatment phase (Vrijens et al., 2012). These difficulties in patient adherence can be mitigated by reducing dose cycles, which is made possible by drug-delivery devices with extended-release properties. As an example, it was observed that male patients on long-term antihypertensive treatment had 80% adherence with a single daily dose compared to 59% with multiple doses using such approach (Eisen et al., 1990). In contrast, patients on a three-doses-per-day chemotherapy regimen exhibited a reduction in adherence (Noens et al., 2009). Therefore, the DDS that can demonstrate sustained, prolonged drug release would provide further benefits from a therapeutic and physiological perspective.

The development of porous scaffolds that imitate the structure, mechanical properties, and physical characteristics of natural bone has been the focus of recent developments in bone tissue engineering. These scaffolds facilitate functional cell processes, which are essential for tissue regeneration, while also offering structural support (Mooney et al., 1996; Schultz et al., 2014). The chemical composition and hierarchical structure of bone tissues and the synergistic effect of cells and scaffolds toward bone regeneration are illustrated in Figure 2. The efficacy of porous scaffolds in facilitating cellular interactions, maintaining tissue volume, and transporting biological agents has been demonstrated in a variety of previous studies. Currently, various techniques have been implemented to incorporate drug delivery capabilities into bone scaffolds. These include loading drug molecules in the interparticle porosity of bioceramic scaffolds (Bigham et al., 2019), drug loading into a polymer matrix (Abdal-Hay et al., 2013), surface coating of some porous or mesoporous nanoparticles which have a great potential for high drug loading followed by prolonged release (Bigham et al., 2016; Bigham et al., 2020). Researchers interested in osteosarcoma treatment are drawn to implantable drug delivery technology because of its benefits over more traditional approaches like oral or parenteral dosage forms. With the aid of such technology, antitumor medications can be released gradually over weeks, months, and occasionally even years (Meng & Hoang, 2012). The implantable entity also functions as a localized drug delivery system that maximizes the concentration of drug at the desired site while minimizing systemic drug exposure and adverse side effects (Zhou et al., 2015). The gentamicin bead chain, developed by Klemm in the 1980s, was the first therapeutic use of locally implantable drug carriers (Klemm, 2000). Researchers developed drug-loaded implants for local tumor chemotherapy in response to this study. According to Fournier et al., the implant can stop tumor cells from growing within 0.5–5 cm of the implant (Fournier et al., 1991). To achieve local treatment, the active drugs are mixed with a biocompatible carrier by the drug-loaded implants, capable of slowing drug release upon insertion into the body. On account of its high local drug concentration along with a low systemic blood drug concentration, desirable anti-tumor efficacy, and fewer side effects, local chemotherapy is becoming more and more popular among academics and doctors. Conventional implantable materials, however, could only transport a single medication. Its clinical application is also constrained by the inability to customize care as well as the need for secondary surgery. Biocompatibility, bioactivity, and biodegradability are all essential factors that must be taken into account when fabricating desired implantable drug delivery systems for the therapy of osteosarcoma (Choi et al., 2007; Zhou et al., 2017; Kabb et al., 2018).

Figure 2. The hierarchical anatomy structures of bone tissues. The synergistic effect of cells and scaffolds comprises a bone regeneration strategy. Reproduced from Chen et al. (2018) under the terms and conditions of the creative commons attribution (CC by 4.0 DEED) license (http://creativecommons.org/licenses/by/4.0/).

Due to the limitations of current osteosarcoma treatments, researchers are looking into new and more effective approaches. As a result, several cutting-edge strategies using scaffolds for localized sustained treatment have been suggested. Structural elements or implants can be constructed using additive manufacturing techniques, which offer the advantages of substantial customization, reproducibility, and cost-effectiveness. These cutting-edge medicinal techniques appear to be promising avenues for future osteosarcoma therapy and post-therapy bone regeneration. In this review, a thorough overview of novel therapeutic strategies using additively manufactured 3D clinical implants as local cancer treatment substrates is provided.

4. Study methodology

4.1. Inclusion/exclusion criteria

The inclusion criteria were as follows:

4.1.1. Inclusion criteria

In conducting this review, specific inclusion criteria was used to ensure the selection of relevant and high-quality studies. Firstly, studies were included if they specifically addressed osteosarcoma and its treatment using bone scaffolds as drug delivery systems. We considered peer-reviewed articles, reviews, and conference proceedings to include scholarly works. English-language publications were included to maintain consistency and accessibility.

4.1.2. Exclusion criteria

To maintain the focus of the review and ensure the reliability of the selected studies, exclusion criteria were implemented. Studies that did not specifically involve bone scaffolds for drug delivery in the context of osteosarcoma were excluded. Publications with low relevance to the main theme of the review or those that did not contribute significantly to the understanding of localized drug delivery for osteosarcoma were also excluded. Furthermore, we limited our inclusion to studies published within a certain timeframe (from inception to October 2023) to capture the most recent developments while excluding outdated information.

4.2. Search strategies and relevant studies selection

To identify relevant studies for this review, a systematic literature search was conducted using carefully crafted search strings. The search aimed to cover the current literature on bone comprehensively scaffold-based localized drug delivery for osteosarcoma. The following search string was employed:

‘(Osteosarcoma OR bone neoplasm) AND (localized bone scaffolds OR drug delivery systems) AND (Natural polymers OR Synthetic polymers).’

4.3. Online database searches and data retrieval

The search was conducted in major academic databases, including but not limited to PubMed, Scopus, Google Scholar, NCBI, and Web of Science. Additionally, the reference lists of identified articles and relevant reviews were manually searched to ensure the inclusivity of the review. To ensure a comprehensive review of the literature, our systematic literature search covered multiple databases widely recognized in the academic and scientific community. We included PubMed as a primary database for biomedical literature, given its extensive coverage of peer-reviewed journals in medicine and life sciences, making it a valuable resource for capturing a broad range of articles related to osteosarcoma, bone scaffolds, and drug delivery systems. Scopus, a multidisciplinary abstract and citation database, was included to ensure comprehensive coverage of scientific literature and access to a diverse range of journals, conference proceedings, and patents. Web of Science was selected for its comprehensive coverage across various disciplines and its ability to facilitate citation tracking, which is crucial for identifying seminal papers and tracking the impact of research over time. This combination of databases was thoughtfully selected to maximize the scope and depth of our literature search, ensuring the inclusion of relevant studies in the interdisciplinary context of localized drug delivery for osteosarcoma.

5. Bone scaffold as drug delivery system

A bone scaffold is a transient mechanical structure that mimics the extracellular matrix (ECM) of bone tissue. Its primary objective is to provide an environment beneficial to bone remodeling and regeneration without causing significant complications as shown in Figure 3 (Wubneh et al., 2018; Alonzo et al., 2021). The utilization of bone scaffolds as local drug delivery systems (DDS) represents an innovative and fascinating bone tissue enginnering strategy. The treatment of bone diseases frequently poses challenges due to the avascular circumstances present in the adjacent cartilage (Nadar et al., 2020). Drug delivery to the intended site via bone scaffolds permits high concentrations of the drug at the site of action, thereby reducing systemic absorption and, consequently, drug toxicity, while maintaining the space necessary for the formation of new, healthy bone (Martin & Bettencourt, 2018; Nadar et al., 2020). Furthermore, this methodology facilitates the administration of hydrophobic drugs and provides sustained drug delivery. Furthermore, the enhancement of drug delivery efficacy allows for a decrease in both the frequency of dosing and the quantity of therapeutic agents, ultimately resulting in better patient compliance (Nadar et al., 2020). There has been significant focus on improving the effectiveness of scaffolds by incorporating biomolecules like growth factors or drugs. This process is carried out to treat bone disorders or target surrounding tissues with an appropriate amount of drugs for a particular period of time (Mouriño & Boccaccini, 2010). Hence, drug-loaded bone scaffolds provide a promising prospective in bone tissue engineering that combines two essential components—the unique anatomical properties of bone tissue and the ability to overcome an important challenge (Moore & Luu, 2014). The scaffold functions as an appropriate structural tool to facilitate bone remodeling and repair. As drug-loaded bone scaffolds function as localized DDS, they are capable of targeting bone tissue locally and specifically, thereby facilitating further treatment of the injured area and promoting the healing process (Sarigol-Calamak & Hascicek, 2018). It could stop the spread of the tumor, and lessen the side effects of the chemotherapy regimen while repairing the bone flaw left behind by the tumor removal (Liao et al., 2021).

Figure 3. Representation of three-dimensional bone bioactive scaffolds and their origin.

Three-dimensional bone bioactive scaffolds can be produced using an extensive range of bulk biomaterials; however, bio-ceramics (e.g. fibrin, collagen, tricalciumphosphate, bio-glasses], and biodegradable synthetic and natural polymers (e.g. collagen, fibrin, chitosan or polyesters, polydioxanone, polyethylene glycol (PEG)) are particularly regarded as promising scaffold materials. Specifically, their composites for bone tissue engineering represent an optimized and viable alternative by combining the benefits of bioactive ceramics and biodegradable polymers.

5.1. Bioceramics scaffolds

Bioceramics are ceramic substances that were developed specifically for use in the medicinal industry. Because of their mechanical rigidity and inorganic constitution, bioceramics have been extensively used in the engineering of hard tissues. The most popular bone substitutes in bone tissue engineering are calcium phosphates (CaPs) and calcium silicate because of their superior biocompatibility as well as their compositional similarity to bone minerals (Cuylear et al., 2023). Hydroxyapatite, tricalcium phosphate, and biphasic calcium phosphate are among the calcium phosphates family of bioceramics. Calcium phosphate ceramics do not have osteoinductive properties in their non-porous and solid states. However, this can be modified through the implementation of surface modification techniques, such as the introduction of macroscopic and microscopic pores, ensuring the scaffold possesses the appropriate roughness, and modifying the surface morphology (Samavedi et al., 2013). The surface charge and chemistry of calcium phosphates are the main factors responsible for the osteoinductivity of calcium phosphates (Xiao et al., 2020). Additionally bioresorbable are phosphate bioceramics. Compared to calcium phosphate bioceramics, calcium silicate bioceramics have better mechanical characteristics. The silicon-rich layer existing on the surface of the bioceramic causes apatite formation. Because of their exceptional interfacial bonding with natural tissue, silicate bioceramics are bioactive (Venkatraman & Swamiappan, 2020).

Owing to its extraordinary biocompatibility, low biodegradability, non-toxicity and immunogenicity, strong affinity for bone tissue, and non-inflammatory characteristics, hydroxyapatite (HA), a mineral matrix made of Ca10(PO4)6(OH)2 that has a close resemblance with the crystallographic structure of teeth and bone, is frequently employed as a synthetic bone graft (Avanzi et al., 2023). Zakeri et al. reported the manufacture of polycaprolactone-zeolite nanocomposite Y (PCL-Zeol) scaffold for cisplatin’s sustained release for the therapy of bone cancer (Figure 4) (Zakeri et al., 2022). The findings showed that, based on the Zeol content, scaffolds with an open-pore diameter in the range of 200–400 μm and a considerably high net porosity were developed. After an early burst release of Cis, the PCL-Zeol nanocomposite scaffold may offer a pH-sensitive sustained release of Cis following 7 d. It was therefore concluded that PCL-Zeol-Cis scaffolds with appropriate mechanical properties, substantial bioactivity, and cytotoxic activity could be helpful for the efficient treatment of bone imperfections resulting from surgery for the treatment of bone cancer and could prevent the recurrence of cancer cells. The regulated release of bisphosphonates for osteoporosis was also accomplished through the development of chitosan calcium zeolite scaffolds (Sandomierski et al., 2022). The chitosan-HA scaffold has been used to compare their properties. Researchers showed that zeolite scaffolds were superior to HA scaffolds in terms of drug retention. More medication was released from the hydroxyapatite scaffold after 30 d, the dose released on the first day was around half of the total amount present; this ‘burst release’ phenomenon is not ideal with such pharmaceuticals. The addition of zeolite to the scaffold allows for the controlled release of the drug at a steady rate. Bisphosphanates have been shown in preclinical studies to have direct antitumor effects on a range of human cancer cells, and it is known that they reduce cell growth in human osteosarcoma cell line panels, disrupt the cell cycle, and induce SaOS-2 cell’s apoptosis (Evdokiou et al., 2003; Kubo et al., 2006). Hence the develpped chitosan-calcium zeolite could be advantageous in the treatment of osteosarcoma.

Figure 4. The schematic illustration of (a) the cis loaded zeol nanoparticles, (b) the fabrication of PCL – zeol – cis scaffolds, and (c) implantation of PCL – zeol – cis scaffolds in bone defect and the subsequent performance. Reproduced from Zakeri et al. (2022) under the terms and conditions of the creative commons attribution (CC by 4.0 DEED) license (https://creativecommons.org/licenses/by/4.0/.).

The fabrication of appropriate 3D-printed scaffolds has the potential to not only repair bone defects brought on by bone tumors, they additionally inhibit tumor cells, delayed tumor growth, and ultimately stop bone tumors from returning and spreading. 3D printing, a type of additive production, enables product parameter customization. For example, structures with controlled hydroxyapatite components were made using 3D high-resolution (<210 m) printing at room temperature. In an attempt to develop bioceramic scaffolds with various amounts of hydroxyapatite for enhancing the scaffolds’ osteoclast activity, mechanical properties, and porosity, Yoontae Kim et al. adjusted the formation rate and quantity of hydroxyapatite via adjustment of the concentration of Na2HPO4 (Kim et al., 2022). Dang et al. successfully combined the photothermal treatment and chemotherapy for osteosarcoma via a continuous coating of tricalcium phosphate (TCP) scaffolds with doxorubicin (DOX) and TiN microparticles (Dang et al., 2021). The amount of DOX and TiN existing within the scaffold could be changed by submerging it in a solution with various TiN and DOX amounts. Time-dependent release of DOX was observed from the scaffolds with a maximum release of around 60% at 48 h. Local controlled-release chemotherapy and precision photothermal therapy have both demonstrated effective curative outcomes in vitro and in vivo. Moreover, mesoporous bioactive glass (MBG) is the subject of the current study. Compared to traditional bioactive glasses, MBG has a significantly higher surface area and pore volume thanks to its ordered mesoporous (nanoporous) structure. It is a rather straightforward strategy to functionalize sub-microparticles for various drug delivery applications because MBG surfaces contain silanol groups. For local drug delivery, M. Ravanbakhsh et al. produced submicron MBG particles that were uniform with respect to structure and size (Ravanbakhsh et al., 2019). Because the surface of MBG is negatively charged, researchers incorporated amine groups to achieve a positively charged surface in an attempt to increase the effectiveness of drug attachment and loading.

5.2. Natural polymer-based scaffolds

Natural polymers consist primarily of polysaccharides (chitosan, hyaluronic acid, alginate, and cellulose) and proteins (collagen, silk fibroin). Usually, they comprise biofunctional molecules that ensure natural remodeling, biomimetic surface, and bioactivity (Chocholata et al., 2019). Scaffolds composed of natural polymers have been shown to facilitate the differentiation of mesenchymal stem cells into osteoblasts and to be highly biocompatible. However, naturally derived biomaterials exhibit a reduced degree of control over their mechanical properties and biodegradability in contrast to synthetic polymers (Yarlagadda et al., 2005).

Collagen is one of the most extensively investigated natural polymers utilized in biomedical applications. It is recognized for promoting the deposition of mineralized matrix and providing a number of favorable binding sites for bone cell adhesion as a fundamental component of numerous animal tissues (Ferreira et al., 2012; Zhang et al., 2018). Collagen serves as a surface for cell adhesion and makes a great scaffold for mineralization. Native collagen lacks mechanical strength, but it can be combined with other biopolymers to make up for this and improve mechanical strength while also enhancing cellular activity (Lee et al., 2018) (Figure 5). Collagen Type I fibril represents greater than 90% of the organic matrix of bone and composed of five triple-helical collagen chains. Porous collagen scaffold materials that mimic osteogenic components have been developed in order to promote the development of vasculature within the material and establish an optimal environment for bone formation (Yu et al., 2020). According to Walsh et al., the porous collagen-HAP scaffold could enable the simultaneous transport of two growth factors for healing critical-sized bone defects namely; vascular endothelial growth factor (angiogenic) and bone morphogenetic protein-2 (osteogenic) with sustained release of therapeutic proteins over a prolonged 30-day period (Walsh et al., 2019). In the research by Montalbano et al., a hybrid system was developed using 3D-printed scaffolds made from collagen Type I (with bioactive components like mesoporous bioactive glass containing strontium) that are capable of releasing strontium ions within three days of incubation (Montalbano et al., 2018). The results of the bioactivity revealed that the acidic groups present in the collagen fibers provided a greater number of sites for hydroxyapatite nucleation. This modification potentially enhanced the bioactivity of the constructs.

Figure 5. Schematic representation of the fabrication process of collagen, CE, and CES scaffolds. (a) Decellularization process using MC3T3-E1 cells, (b) SF fabrication, (c) scaffold fabrication employing a low-temperature 3D printing process. Reproduced with permission from Lee et al. (2018) copyright 2018, Elsevier.

Gelatin is a collagen derivative produced from bovine collagen through partial acid (type A) or alkaline (type B) hydrolysis (Hoque et al., 2015). While type B gelatin has been employed in the extended-release of basic molecules, type A gelatin may be used as a vehicle for acidic proteins in vivo (Echave et al., 2017). Gelatin must be crosslinked to enhance its mechanical and thermal characteristics for in vivo applications. Due to the RGD sequences in its primary structural framework, gelatin has several advantageous properties compared to collagen, including reduced immunogenicity and several positive characteristics like elasticity and cell adherence (Su & Wang, 2015; Echave et al., 2017). A larger value of mechanical strength was observed during the extraction of gelatin at a lower temperature, but it was insufficient for use in bone tissue engineering or regeneration (Kuttappan et al., 2016). To overcome this challenge, Kim H. et al. used extrusion printing to develop mixed gelatin/PVA scaffolds using various gelatin: PVA ratios. They concluded that the optimal gelatin: PVA ratio for mechanical strength, cell growth, and differentiation is 5:5 (Kim et al., 2018). Chuan Chen et al. introduced a novel approach for the treatment bone osteosarcoma by utilizing a multipurpose scaffold designed specifically for localized drug delivery (Chen et al., 2019). The preparation of two different forms of drug-releasing regenerative scaffolds—adriamycin poly (dl-lactide-co-glycolide) gelatin microspheres and adriamycin gelatin microspheres—and their anchoring to D-periosteum. The obtained results demonstrated the scaffolds’ capacity to prolong the drug release and to stop the development of cancer cells in vitro.

Deacetylated chitin, a polysaccharide primarily derived from the bones of crustaceans, is known as chitosan (CS) (e.g. crabs and shrimp). Mucoadhesion, controlled drug release, in-situ gelation, permeation enhancement, transfection, and efflux pump inhibitory effects are all made possible by the cationic character of CS (Mekhilef et al., 2012). The CS-based scaffolds are a prospective candidate for the delivery of therapeutic agents to the defect site in a targeted and controlled manner. CS hydrogel has been prepared that is capable of long-term release of the active substance (Jakubowski et al., 2023). Composites made from CS have received extensive research as bone regeneration substrates. A lanthanum-modified chitosan matrix hydrogel material has also been discovered, which could serve as an implanted hydrogel capable of sustained and gradual release of bisphosphonates (Jakubowski et al., 2023). The authors have indicated that the proportion of 35% of the drug was released over 51 days. The medicine was released gradually, with no sudden bursts of the first dose therefore, avoiding the danger of harming healthy cells. Due to these attributes, the substance is suitable to be employed as a hydrogel implanted in the treatment of bone disease or as a coating for bone prostheses. The progressive release of the drug could be facilitated by the implantation of such a substance at the site of the affected bone. Dornjak et al suggested the treatment of tumor residues after surgical resection of the tumor using chitosan-based scaffolds as potential DOX DDSs (Dornjak et al., 2022). DOX was effectively encapsulated using chitosan and genipin crosslinking reactions, while maintaining the scaffold-based DDS’s extremely porous and interconnected structure. Boric acid, a source of the bioactive agent boron, was used to concurrently modify scaffolds in order to provide angiogenic potential to the scaffolds, thereby extending the functionality of drug carriers. To promote tumor inhibition and, chitosan-based scaffolds were developed. However, the scaffold exhibited the rapid release of DOX till 6 h of investigation.

Alginate is a biopolymer made from brown algae that might need to be further purified before it can be used for bone regeneration (Torres et al., 2019). Alginates can be used as bioinks to develop supports for 3D printing by ionic crosslinking them with divalent cations to create hydrogels (Hernández-González et al., 2020). Alginate typically lacks both the biological characteristics that can hasten bone development and the necessary mechanical strength. Alginates, however, have continued to be used in bone regeneration because they are effective transport systems of peptides like BFP-1 (Heo et al., 2019). BMP-2 activity was prolonged by adding sulfate entities to alginate in bio-inks for 3D printing (Park et al., 2018). To effectively treat osteosarcoma, Yanshan Sheng et al. reported the development of a dual-drug delivery scaffold made of carboxymethyl chitosan and oxidized alginate that can transport methotrexate and naringin in response to different stimuli (Sheng et al., 2022). According to the cytotoxicity findings, the dual-responsive DDS exhibited a considerable growth inhibitory influence on Saos-2 osteosarcoma cells when exposed to NIR radiation, indicating that it may be a prospective candidate to be used in osteosarcoma treatment (Figure 6).

Figure 6. Schematic illustration of the preparation of the dual-responsive drug delivery scaffold composed of oxidized alginate and carboxymethyl chitosan. Reproduced with permission from Sheng et al. (2022), copyright 2022, Elsevier.

5.3. Synthetic polymers-based scaffolds

Synthetic polymers have demonstrated considerable potential as biomaterials in the field of bone tissue engineering owing to their biodegradable and biomechanical characteristics. Furthermore, they offer enhanced controllability with respect to immunological adverse effects, physiochemical structure, and porosity in comparison to other types of scaffolds (Fuchs et al., 2001; Kretlow & Mikos, 2007). For instance, by developing the polymers’ functional groups, it is possible to alter the characteristics of a polymer scaffold, such as porosity, degradation capability, and mechanical strength (Radulescu et al., 2022). Due to their tunable biodegradability, low toxicity, and possible ability to produce porous scaffolds, poly(ε-caprolactone) (PCL), polyurethane, polylactic acid (PLA), and polyvinyl alcohol (PVA) are the frequently used synthetic polymers (Chocholata et al., 2019). Despite not being osteoconductive, PCL can be altered to become both osteoconductive and osteoinductive, for instance by adding growth factors (Burnett et al., 2002). In craniofacial surgery, 3D-printed PCL scaffolds are offered as biodegradable implants. Sagnik Ghosh et al. investigated the formation of PCL frameworks with hierarchical pores using 3D printing (Figure 7) (Ghosh et al., 2023). For use in in vitro bone regeneration, these scaffolds displayed the ideal porosity, density, cytocompatibility, and mechanical characteristics. To facilitate the assessment of potential novel treatments and the investigation of tumor progression, an effort is made to replicate an osteosarcoma model by enriching the osteo-differentiated human mesenchymal stromal cells utilized in the 3D printed polyurethane scaffolds with in vitro pre-generated bone extracellular matrix.

Figure 7. Schematic showing the 3D printing process used to produce nanoclay-enriched PCL hierarchical porous scaffolds. Reproduce with permission from Ghosh et al. (2023), copyright 2023, American chemical society.

Poly (lactic acid) (PLA) is a thermoplastic biopolymer, whose stereochemistry influences its characteristics. PLA’s hydrophobicity resulted in a sluggish rate of biodegradation as well as reduced cell adhesion. The accumulation of lactic acid during biodegradation might cause inflammatory responses. These limitations could be overcome via the incorporation of buffers to the scaffold matrix to prevent the production of lactic acid as well as other bioactive materials to improve cell attachment and osteoconductivity (Tajbakhsh & Hajiali, 2017). The inclusion of MgO and halloysite nanotubes has been investigated as a means of buffering the lactic acid biodegradation products to enhance osteogenic activity and the mechanical strength of PLA. MgO promoted cell adhesion, proliferation, and differentiation while Halloysite nanotubes improved scaffold strength (Liu et al., 2020). Mixed matrix scaffolds based on poly (L-lactic acid)/mesoporous bioactive glass composite were developed by Shubham Pant et al., and they resemble the composition of natural bone (Pant et al., 2022). The in-vitro bioactivity evaluation revealed that apatite crystallized quickly, reaching a Ca/P ratio of 1.66 equal to natural bone mineral on the third day of treatment with simulated body fluids. In terms of cell attachment and proliferation, gene expression as well as mineralization features, the scaffold responded favorably to in vitro biological testing using MG-63 osteosarcoma cells. The therapeutic benefits of high-dose doxorubicin infusion are significantly hampered by drug resistance and side effects. Lei Zhang et al. developed an injectable rhein (RH)-assisted crosslinked hydrogel to treat osteosarcoma effectively and safely. The hydrogel was formed by adding doxorubicin and rhein to a PVA solution (Figure 8) (Zhang et al., 2023). The results of the transwell and wound healing tests showed that hydrogel could greatly reduce osteosarcoma cell invasion and metastasis. After a single dose of hydrogel was injected, it demonstrated a long-lasting antitumor effect that greatly reduced osteosarcoma growth and metastasis, fulfilling the goal of one-time administration for long-term treatment. Interestingly, rhein promoted PVA crosslinking, which promoted hydrogel formation. In addition, RH showed a burst release of 80% till 24 h, but DOX showed an initial burst release, followed by a slower sustained release for up to 9 days. These findings proved that PRDH injections near the tumor site resulted in persistent, prolonged drug release. The system offers an alternative therapy and broadens the options for osteosarcoma clinical treatment.

Figure 8. The preparation process and antitumor mechanism of the hydrogel. (A) The preparation process of the hydrogel. Using a PVA solution for freeze-thaw, doxorubicin, and rhein were combined to form an injectable hydrogel with shear-thinning characteristics. (B) a single peritumoral injection of hydrogel was given using a needle with an internal diameter of 0.45 mm. Doxorubicin and rhein were slowly released following a single injection, successfully preventing osteosarcoma proliferation and inducing apoptosis. Reproduced with permission from Zhang et al. (2023). copyright 2023, Elsevier.

5.4. Nano/microparticle-containing scaffolds

Over the last few decades, there has been a notable focus on drug delivery systems using nano/microparticles. These vehicles not only protect the loaded drugs but also function as localized scaffolds, controlling the release kinetics. These attributes enable achieving the same treatment effect with lower drug dosages, thereby minimizing potential side effects (Sangi et al., 2018). Scaffolds that incorporate nano- or microparticles are typically inorganic-organic hybrid scaffolds. For bone tumor therapy, bifunctional hybrid scaffolds containing particles furnish the ideal construct (Saber-Samandari et al., 2019). Microspheres based on Doxorubicin (DOX)-loaded calcium phosphate-phosphorylated adenosine were fabricated for treating bone tumors (Figure 9) (Zhou et al., 2017). Microspheres’ pH-sensitive characteristics had a beneficial medicinal impact on rats’ subcutaneous 143B osteosarcoma tumors. In addition, the hybrid microspheres can actively facilitate the osteogenic differentiation in culture via the production of certain kinds of molecules. These in vivo findings confirmed the efficacy of the sustained-release CPPA-DOX delivery approach against tumors, with no obvious systemic side effects. The research demonstrates that calcium phosphate phosphorylated adenosine microspheres may be used for bone repair and tumor prevention. A distinct investigation involved the application of carbon aerogel containing beta-tricalcium phosphate bioceramic (β-TCP) materials, which were originally designed for the treatment of MNNG/HOS osteosarcoma tumors (Dong et al., 2020). In a calvarial defect model, the surface area and roughness of β -TCP was sufficiently improved by the carbon aerogel coating, leading to the effective regeneration of bone tissue.

Figure 9. Illustration of possible applications for CPPA hybrid microspheres in the treatment of osteosarcoma and improved osteogenic differentiation for bone regrowth. After the osteosarcoma was removed, CPPA/DOX microspheres might be placed to the probable residual margin. After releasing the DOX, the microspheres themselves could promote the hBMSC differentiation into osteoblasts, which would then improve bone formation and accelerate bone regeneration. Reproduced with permission from Zhou et al. (2017). copyright, 2016 Elsevier.

Recent developments in magnetic nanoparticle research have shown their high photothermal conversion capability as well as their non-toxicity. In addition to significantly promoting stem cell osteogenic differentiation via activation of the BMP-2/Smad/Runx2 pathway, Lu et al. fabricated magnetic NP-modified porous scaffolds capable of strengthening the thermotherapeutic influence on the tumor, by raising the temperature of osteosarcoma tissue by 42 °C–50 °C under the influence of NIR light (Möller et al., 2016). In a different research, paclitaxel (PTX) was loaded onto novel, magnetically targetable SPIONs surface made of β-cyclodextrin (CD) modified magnetite (Fe3O4) NPs. Under the influence of an applied magnetic field, the Fe3O4@-CD/PT NPs exhibited a noticeably higher affinity for tumor cells (Puiu et al., 2021). Given this evidence, magnetic NPs might be more effective than conventional chemotherapy due to their advantages in delivering localized hyperthermia, delivering targeted drug delivery, and having a magneto-mechanical impact on cancer cells.

Because of its exceptional biocompatibility and thermal conductivity, graphene oxide (GO) can help human bone marrow stromal cells development, differentiation, and expression of osteogenic genes (Su et al., 2020). Additionally, GO has a high infrared (IR) absorption capability and demonstrates photothermal effects when exposed to 808 nm radiation (Wang et al., 2017). To improve the antitumor effect of conventional medications, GO NPs loaded with photosensitizers and drugs can produce a combinatorial chemical-photothermal-photodynamic effect locally. By applying a minimal quantity of magnetic particles to the porous scaffold surface, Zhang et al. developed a magnetic scaffold containing GO NPs (Zhang et al., 2016). For osteosarcoma cells (MG-63) in vitro, the outstanding hyperthermal influence of scaffolds caused more than 75% cell death. The scaffolds significantly increased the osteogenic gene expression and alkaline phosphatase activity of rabbit bone marrow stromal cells (rBMSCs) and accelerated their proliferation. The simultaneous integration of bioactivity and photothermal therapy for bone regeneration into a singular material is another intelligent tactic. Enhanced remineralized bone tissue and photoinduced heat are provided by bismuth (Bi)-doped bioglass (Wang et al., 2018). This research was the first to mention Bi’s high photothermal conversion. The radiative and nonradiative processes were managed to regulate the photothermal effects. Bi-hybrid bioglass effectively destroys bone tumors under NIR radiation. Furthermore, Bi facilitates the osteogenic cell growth, division, and mineralization.

6. Stem cells based therapeutic approach

Stem cell treatments are developing as a possible cancer treatment approach. Various types of stem cells have demonstrated an inherent tendency to migrate toward tumors. Furthermore, when these pathotropic delivery vehicles are engineered to express therapeutic agents, they can efficiently target malignant sites. Many adult stem cells (SCs) have innate tumor-tropic features, making them appealing candidates for anticancer biological agent delivery. SCs can diffuse solid tumors and move to micrometastatic lesions, allowing for site-specific administration. The short half-lives of many chemotherapeutic drugs can be avoided by modifying SCs to consistently express or release a variety of anticancer medicines (Abbasi et al., 2020). Human pluripotent stem cell (hPSC) and multipotent mesenchymal stem cell (MSC)-based therapy has been emerging as a major player in regenerative medicine. Since MSC can be loaded with therapeutic drugs while still being able to travel to disease site, they may constitute a perfect vehicle for targeted drug delivery (Hall et al., 2007; Hu et al., 2010). MSC are primary cells that can be grown ex vivo to clinically significant numbers. They can be identified in a variety of tissues, including bone marrow, fat, and muscle (Pittenger & Martin, 2004), and these cell types play an important role in tissue regeneration and repair (Dozza et al., 2011).

MSCs possess tropism toward tumor stroma. By focusing on this particular attribute, it becomes possible to effectively incorporate therapeutic agents into MSCs and utilize their anti-cancer properties to a greater extent. In a study, murine ASCs were subjected to transfection with the complete human TRAIL (TNF-related apoptosis-inducing ligand) gene, a known inducer of apoptosis in osteosarcoma (OS) cells (Grisendi et al., 2015). The in vitro experiment demonstrated that TRAIL conveyed by MSCs significantly induced the SAOS2 apoptosis via caspase-8 activation (Hass et al., 2011). Furthermotre, it has been observed that MSCs can inhibit OS development and bone degradation after being transfected with adenoviruses containing the osteoprotegerin gene (Qiao et al., 2015). MSCs can be manipulated to transport medicine in addition to being transfected with pro-apoptosis genes. With the incorporation of core-shell PMMA nanoparticles (FNPs) post-loaded with a photosensitizer, specifically meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS), into MSC, a novel tri-component biomaterial system was developed for the targeted photodynamic therapy of osteosarcoma (Figure 10) (Duchi et al., 2013). Laser confocal microscopy and time-lapse imaging revealed that the laser irradiation of co-cultures of MSC loaded with photosensitizer-coated fluorescent NPs (TPPS@FNPs) causes cell death and the release of reactive oxygen species (ROS), which is sufficient to trigger cell death of all OS cells (U2OS-RFP-TUBA1B). Stefania et al. investigated the inherent capacity of MSCs to migrate and infiltrate the tumor stroma, to deliver therapeutic drugs to cancer cells with pinpoint accuracy (Lenna et al., 2020). The authors’ goal was to examine the efficiency of photoactivation of nanoparticles loaded with MSCs in vitro and in a mouse in vivo ectopic osteosarcoma model. High levels of in vitro OS cell death were generated by photoactivation of AlPcS4@FNPs-loaded MSCs. After two cycles of photoactivation, MSCs loaded with AlPcS4@FNPs reduced OS growth by 68% in an in vivo ectopic OS model. In addition to cytotoxic and viral vectors, MSCs have been found to carry anti-angiogenic and immunostimulatory therapeutics to tumor sites (Dozza et al., 2011). Transduced MSCs expressing specific anti-cancer molecules like TRAIL, OPG, IL-12, or the CD/5-FC prodrug preferentially to the tumor site imply that MSCs may be ideal for drug delivery in OS. Nevertheless, further investigation is necessary to enhance the engraftment efficacy of MSCs within tumor tissues. The first human clinical trial using autologous bone marrow-derived MSCs harboring oncolytic virus has demonstrated promising outcomes in the treatment of children malignancies, including various sarcomas (Ruano et al., 2020). Increased immune infiltration and decreased tumor growth have been shown in preclinical testing of osteosarcoma using MSCs expressing oncolytic virus in combination with granulocyte-colony stimulating factor (Morales-Molina et al., 2021). Various types of bone scaffolds used for the treatment of osteosarcoma are summarized in Table 1.

Figure 10. Photoactivation of TPPS@FNPs loaded MSC in co-culture with U2OS cells to measure the amount of cell death following photostimulation by exposing cells to 0.02 J/s 405 nm laser for the indicated time points in the selected areas. Reproduced with permission from Duchi et al. (2013). copyright, 2013 Elsevier.

Table 1. Examples of bone scaffolds used for the treatment of osteosarcoma.

Scaffold Material	Drug/Active material	Release time/Therapeutic improvement	Characteristic/Advantage	Reference	
PCL-zeolite nanocompositeY	Cisplatin	After an early burst release, the zeolite exhibited pH sensitive sustained release for 7 days.	PCL-Zeol-Cis scaffolds could be helpful for the efficient treatment of bone imperfections resulting from surgery for the treatment of bone cancer and could prevent the recurrence of cancer cells	(Zakeri et al., 2022)	
Chitosan-calcium zeolite scaffolds	Bisphosphonates	Zeolite scaffold exhibited sustain release till 30 days without any burst release	The developed scaffold offered tremendous potential for the controlled release of bisphosphanates for osteoporosis and bone tissue engineering.	(Sandomierski et al., 2022)	
3D-printed HA bone scaffolds	Na2HPO4, as an accelerator	N/A	Higher TRAP activity and osteoclast expression were observed in cells seeded on HA scaffolds printed in 0.5 mol/L Na2HPO4 solution.	(Kim et al., 2022)	
Doxorubicin and TiN microparticles coated Tricalcium phosphate scaffolds	Doxorubicin	Time-dependent DOX release was observed with a maximum release of around 60% at 48 h	When scaffolds were implanted into bone deficiencies caused by the removal of osteosarcoma, the overall bulk of the scaffolds provided mechanical support for bone tissue.	(Dang et al., 2021)	
Gelatin/PVA scaffolds	The benefits of PVA and gelatin were investigated for bone tissue engineering	N/A	Gelatin/PVA (5:5) was the optimal weight fraction for increased cell proliferation and differentiation, revealing the significance of harmony between physical and biological components in bone formation.	(Kim et al., 2018)	
Gelatin/decellularized periosteum-based biologic scaffold	Adriamycin	Around 65% ADM was released in the first 24 h, with 80% cumulative release till 48 h	The developed scaffold exhibited the sustained release of the drug with significant inhibition in the growth of the cancer cells in vitro.	(Chen et al., 2019)	
Chitosan-boric acid scaffold	Doxorubicin	The scaffold exhibited the rapid release of DOX till 6 h	The proposed chitosan-based scaffolds were found to be useful for tumor inhibition and tissue regeneration in defects caused by surgical removal of the tumor.	(Dornjak et al., 2022)	
Dual-drug delivery scaffold based	Methotrexate and Naringin	MTX and Nar exhibited 91.09% and 85.69% after NIR radiation	Dual-responsive DDS that was created exhibits a considerable growth inhibitory influence on Saos-2 OS cells when exposed to NIR radiation	(Sheng et al., 2022)	
PLA/MBG composite scaffold	N/A	N/A	The 3D bioprinted PLA/MBG composite scaffold showed promising cell attachment and proliferation, mineralization, and gene expression capabilities in vitro using MG-63 osteosarcoma cells.	(Pant et al., 2022).	
RH-assisted crosslinked hydrogel	Doxorubicin	RH exhibited the burst release of 80% till 24 h with DOX exhibiting sustain release till 9 d	PRDH exhibited low toxicity in both in vivo and in vitro assays, successfully caused apoptosis in OS cells, and dramatically reduced tumor growth.	(Zhang et al., 2023)	
Calcium phosphate-phosphorylated adenosine (CPPA) hybrid microspheres	Doxorubicin	DOX release was observed with 90.04% release at 40 h	The CPPA/DOX drug delivery system demonstrates a discernible therapeutic impact on osteosarcoma in both in vitro and in vivo settings.	(Zhou et al., 2017).	
β-CD-modified Fe3O4 SPIONs for magnetic targeting.	Paclitaxel	N/A	The MG-63 osteosarcoma cell line had 85% of its viability reduced by Fe3O4@-CD/PTX films, exhibiting excellent anti-tumor effectiveness.	(Puiu et al., 2021).	
3D-printed β-TCP bioceramic scaffold modified with Fe3O4 NPs/GO	N/A	b-TCP–8Fe–GO scaffolds maintained sustaine release of Fe ions	The superior hyperthermal effect of -TCP–Fe–GO scaffolds induced greater than 75% cell mortality in osteosarcoma (MG-63) cells.	(Zhang et al., 2016)	
Titanium implants coated with calcium titanate	Bisphosphonates; risedronate	The material exhibited the sustaine release of risedronate for 30 d	A complete release of the active upon contact with body fluids was demonstrated to be possible within a month, confirming the material’s significant promise as a drug carrier in implants.	(Sandomierski et al., 2022)	
Titanium implant coated with hydrogenated black TiO2	N/A	N/A	The 808 nm NIR laser irradiation of the manufactured H-TiO2 coating inhibited tumor growth in vitro and in vivo with excellent and modulatable photothermal effect.	(Zhang et al., 2019)	
Adipose-derived MSC	TRAIL	N/A	MSC-TRAIL persisted in the stroma of pre-established ES xenotransplants, triggering tumor apoptosis compared to controls.	(Grisendi et al., 2015)	
Core-shell PMMA nanoparticles	Photosensitizer; TPP	Actively released TPP till 3.5 min causing the maximum cell death upon photoactivation	When activated with laser light, TPPS@FNPs are efficiently taken up by MSC at 45 g/mL without obvious toxicity, resulting in controlled and prevalent cell death in a short period.	(Duchi et al., 2013)	
AlPcS4@FNPs loaded MSCs	Photosensitizer; AlPcS4	N/A	Photoactivation of MSCs loaded with AlPcS4@FNPs induced a high level of OS cells death in vitro with a 68% decrease in OS growth after two cycles of photoactivation in vivo ectopic OS mode	(Lenna et al., 2020)	

7. Conclusion and future prospectives

In this article, we’ve reviewed some of the most frequently employed bone scaffolds and emphasized a few drug-loading scaffolds for treating bone tumors. The formation of numerous multifunctional drug delivery platforms has made exciting and significant progress, but these platforms are not yet ready for clinical use. The vast majority of these are in the experimental phase employing cells and animals, and they will need a lot of time to transform before being used in clinical settings.

The synthesis of scaffolds with sufficient mechanical properties is an important challenge toward bone relatted disease. The mechanical integrity of the scaffold should be sufficient to enable its functionality within these tissues from the time of implantation until the completion of the remodeling process. Furthermore, scaffolds derived from human or animal sources pose a potential risk of disease transmission (Rimann & Graf-Hausner, 2012). Particularly when animal-derived scaffolds are utilized, the reproducibility of scaffolds throughout samples is unsatisfactory. The development of synthetic or chemically defined scaffolds has emerged as an important area of study in an effort to overcome these limitations. From a therapeutic standpoint, the potential to maximize drug accumulation at the site of action while minimizing dosage and systemic side effects continues to be the greatest challenge to overcome in scaffold-based drug delivery. In accordance with the degradation mechanism of the scaffold material, a number of drug-loaded scaffold systems exhibit an burst release of the incorporated drugs, succeeded by a degradation-mediated release. In such circumstances, modifying the degradation process of the material would enables a certain level of regulation regarding the rate of release (Lienemann et al., 2012). From a manufacturing perspective, NP formulations frequently contain components resembling natural bone structures. This strategy is fundamentally biomimetic and guarantees the scaffolds’ affinities with the target tissue and effective uptake. Furthermore, Moreover, there are numerous benefits associated with the integration of nanoparticles into scaffolds for the purpose of drug delivery such as it can be effectively used to overcome the limitations associated with poor mechanical properties (Jayaraman et al., 2015). Indeed, nanoparticle incorporation into scaffolds has proven to improve the bulk mechanical strength of scaffolds (Corona-Gomez et al., 2016).

The relatively poor mechanical properties of collagen-based scaffolds are one of their limitations; however, hybrid scaffolds that incorporate collagen combine the exceptional biocompatibility of collagen with the enhanced mechanical properties of an alternative material. Additional limitations of collagen include increased production costs and significant in vivo swelling caused by its pronounced hydrophilicity (Ferreira et al., 2012). On Conversely, the insufficient performance of ceramic-based scaffolds in load-bearing applications limits their clinical application. While ceramics are known for their considerable strength, their tendency to be exceptionally brittle poses a significant challenge to the effective regeneration of loaded bone (Fu et al., 2011). To address this challenge, one solution involves the development of ceramic-based composite scaffolds. These systems merge the outstanding biocompatibility of calcium phosphates with the durability of biocompatible polymers. The rationale behind the utilization of composite materials in numerous investigations was to produce scaffolds that more closely resemble the mechanical properties of bone. It is important to consider the negative effects of larger pores on the mechanical characteristics and structural integrity of the scaffold, even though these larger pores promote bone development and vascularization. Bioceramic scaffolds, particularly those composed of materials with higher degradation rates as TCP, should not have porosities more than 90%. Due to the fact that rapid degradation may result in a premature deterioration of the scaffold’s mechanical properties and integrity before an adequate duration for new bone formation (Karageorgiou & Kaplan, 2005)

Bone scaffolds represent an opportunity with unrealized promise. They can serve as prolonged-release platforms for medications that target residual osteosarcoma cells following surgical resection, promote bone regeneration, and reduce infections following surgical scaffold implantation. Currently, there are two ways to accomplish this: directly incorporating the drug into the scaffold (if the drug is appropriate) or incorporating drug-encapsulated nanoparticles into the scaffolds, which can deal with problems such as toxicity and poor solubility that are intrinsic to several drugs. Adjuvant treatment may enable precise targeting of cancer cells through various approach like modifying nanocarriers to react to specific stimuli or labeling nanocarriers with targeting chemicals. In conclusion, is is anticipated that the therapy of bone tumors and related disorders will increasingly depend on nanotechnology. It is expected that after overcoming some of the aforementioned difficulties, improved and optimized nanocarriers can be fabricated for the successful treatment of bone tumors.

Authors contributions

BZ Conceive the idea, Material collection WL: writing the initial draft of the manuscript, HL: writing the initial manuscript; HZ: data gathering and writing the initial manuscript; JB: writing the initial manuscript; HZ: writing, reviewing and editing the original draft; HL: reviewing and editing the original draft, JB: critically reviewed and edited the manuscript and BJ: critically reviewed and edited the manuscript; JW: revised the manuscript and added art work; JZ, writing and editing the revised manuscript; BJ: JW: LF: WM:, JZ: Supervised the project, BZ: Supervised the project. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declared no competing interest.

Data availability statement

Data sharing not applicable – no new data generated.
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