Photo-Cross-Linked Scaffold with Kartogenin-Encapsulated Nanoparticles for Cartilage Regeneration.
Shi Dongquan,Xu Xingquan,Ye Yanqi,Song Kai,Cheng Yixiang,Di Jin,Hu Quanyin,Li Jianxin,Ju Huangxian,Jiang Qing,Gu Zhen
ACS nano
The regeneration of cartilage, an aneural and avascular tissue, is often compromised by its lack of innate abilities to mount a sufficient healing response. Kartogenin (KGN), a small molecular compound, can induce bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes. The previous in vitro study showed that kartogenin also had a chondrogenesis effect on synovium derived mesenchymal stem cells (SMSCs). Herein, we present the effect of an ultraviolet-reactive, rapidly cross-linkable scaffold integrated with kartogenin-loaded nanoparticles using an innovational one-step technology. In vivo studies showed its potential role for cell homing, especially for recruiting the host's endogenous cells, including BMSCs and SMSCs, without cell transplantation. Of note, the regenerated tissues were close to the natural hyaline cartilage based on the histological tests, specific markers analysis, and biomechanical tests. This innovative KGN release system makes the chondrogenesis efficient and persistent.
10.1021/acsnano.5b06663
Porous Silicon-Based Nanomedicine for Simultaneous Management of Joint Inflammation and Bone Erosion in Rheumatoid Arthritis.
ACS nano
The lack of drugs that target both disease progression and tissue preservation makes it difficult to effectively manage rheumatoid arthritis (RA). Here, we report a porous silicon-based nanomedicine that efficiently delivers an antirheumatic drug to inflamed synovium while degrading into bone-remodeling products. Methotrexate (MTX) is loaded into the porous silicon nanoparticles using a calcium silicate based condenser chemistry. The calcium silicate-porous silicon nanoparticle constructs (pCaSiNPs) degrade and release the drug preferentially in an inflammatory environment. The biodegradation products of the pCaSiNP drug carrier are orthosilicic acid and calcium ions, which exhibit immunomodulatory and antiresorptive effects. In a mouse model of collagen-induced arthritis, systemically administered MTX-loaded pCaSiNPs accumulate in the inflamed joints and ameliorate the progression of RA at both early and established stages of the disease. The disease state readouts show that the combination is more effective than the monotherapies.
10.1021/acsnano.2c04491
mPPTMP195 nanoparticles enhance fracture recovery through HDAC4 nuclear translocation inhibition.
Journal of nanobiotechnology
Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.
10.1186/s12951-024-02436-1
Biosynthesized Bandages Carrying Magnesium Oxide Nanoparticles Induce Cortical Bone Formation by Modulating Endogenous Periosteal Cells.
ACS nano
Bone grafting is frequently conducted to treat bone defects caused by trauma and tumor removal, yet with significant medical and socioeconomic burdens. Space-occupying bone substitutes remain challenging in the control of osteointegration, and meanwhile activation of endogenous periosteal cells by using non-space-occupying implants to promote new bone formation becomes another therapeutic strategy. Here, we fabricated a magnesium-based artificial bandage with optimal micropatterns for activating periosteum-associated biomineralization. Collagen was self-assembled on the surface of magnesium oxide nanoparticles embedded electrospun fibrous membranes as a hierarchical bandage structure to facilitate the integration with periosteum . After the implantation on the surface of cortical bone , magnesium ions were released to generate a pro-osteogenic immune microenvironment by activating the endogenous periosteal macrophages into M2 phenotype and, meanwhile, promote blood vessel formation and neurite outgrowth. In a cortical bone defect model, magnesium-based artificial bandage guided the surrounding newly formed bone tissue to cover the defected area. Taken together, our study suggests that the strategy of stimulating bone formation can be achieved with magnesium delivery to periosteum and the proposed periosteal bandages act as a bioactive media for accelerating bone healing.
10.1021/acsnano.2c04747
Electrospun microfiber membranes embedded with drug-loaded clay nanotubes for sustained antimicrobial protection.
Xue Jiajia,Niu Yuzhao,Gong Min,Shi Rui,Chen Dafu,Zhang Liqun,Lvov Yuri
ACS nano
Guided tissue regeneration/guided bone regeneration membranes with sustained drug delivery were developed by electrospinning drug-loaded halloysite clay nanotubes doped into poly(caprolactone)/gelatin microfibers. Use of 20 wt % nanotube content in fiber membranes allowed for 25 wt % metronidazole drug loading in the membrane. Nanotubes with a diameter of 50 nm and a length of 600 nm were aligned within the 400 nm diameter electrospun fibers, resulting in membranes with doubling of tensile strength along the collector rotating direction. The halloysite-doped membranes acted as barriers against cell ingrows and have good biocompatibility. The metronidazole-loaded halloysite nanotubes incorporated in the microfibers allowed for extended release of the drugs over 20 days, compared to 4 days when directly admixed into the microfibers. The sustained release of metronidazole from the membranes prevented the colonization of anaerobic Fusobacteria, while eukaryotic cells could still adhere to and proliferate on the drug-loaded composite membranes. This indicates the potential of halloysite clay nanotubes as drug containers that can be incorporated into electrospun membranes for clinical applications.
10.1021/nn506255e
ON or OFF: Triggered therapies from anodized nano-engineered titanium implants.
Jayasree Anjana,Ivanovski Sašo,Gulati Karan
Journal of controlled release : official journal of the Controlled Release Society
Surface modification of Ti implants has been advocated as a means to augment osseointegration and enable antibacterial functions. Among the various modification strategies, the fabrication of TiO nanotubes (TNTs) on Ti implants via electrochemical anodization has shown promising outcomes. However, such systems do not enable activation, deactivation and tuning of the therapies after the implant placement, in response to local bone microenvironment conditions, to achieve a maximal therapeutic effect. Therapies administered from the implant surface in situ and managed by internal/external triggers can shift the paradigm in providing responsive therapy. In this review, we explore the various triggers that have been employed to achieve triggered therapies from the surface of modified Ti implants, with special focus on TNTs. We critically evaluate the current research advances in this domain (including biological, electrical, magnetic and electromagnetic triggers), cytotoxicity concerns and research challenges that must be addressed to achieve clinical translation of triggered therapies from modified Ti implants.
10.1016/j.jconrel.2021.03.020
Sustained Release of Two Bioactive Factors from Supramolecular Hydrogel Promotes Periodontal Bone Regeneration.
Tan Jiali,Zhang Mei,Hai Zijuan,Wu Chengfan,Lin Jiong,Kuang Wen,Tang Hang,Huang Yulei,Chen Xiaodan,Liang Gaolin
ACS nano
Intact and stable bone reconstruction is ideal for the treatment of periodontal bone destruction but remains challenging. In research, biomaterials are used to encapsulate stem cells or bioactive factors for periodontal bone regeneration, but, to the best of our knowledge, using a supramolecular hydrogel to encapsulate bioactive factors for their sustained release in bone defect areas to promote periodontal bone regeneration has not been reported. Herein, we used a well-studied hydrogelator, NapFFY, to coassemble with SDF-1 and BMP-2 to prepare a supramolecular hydrogel, SDF-1/BMP-2/NapFFY. In vitro and in vivo results indicated that these two bioactive factors were ideally, synchronously, and continuously released from the hydrogel to effectively promote the regeneration and reconstruction of periodontal bone tissues. Specifically, after the bone defect areas were treated with our SDF-1/BMP-2/NapFFY hydrogel for 8 weeks using maxillary critical-sized periodontal bone defect model rats, a superior bone regeneration rate of 56.7% bone volume fraction was achieved in these rats. We anticipate that our SDF-1/BMP-2/NapFFY hydrogel could replace bone transplantation in the clinic for the repair of periodontal bone defects and periodontally accelerated osteogenic orthodontics in the near future.
10.1021/acsnano.9b00788
Osteoconductive hybrid hyaluronic acid hydrogel patch for effective bone formation.
Choi Soojeong,Lee Jong Seung,Shin Jisoo,Lee Min Suk,Kang Donyoung,Hwang Nathaniel S,Lee Hyungsuk,Yang Hee Seok,Cho Seung-Woo
Journal of controlled release : official journal of the Controlled Release Society
Bio-inspired adhesive hydrogels have been applied to cell and drug delivery systems to address various tissue defects and disorders. However, adhesive hydrogels functionalized with phenolic moieties often lack osteoconductive capacity and mechanical properties for bone regeneration. In this study, we utilized the versatile chemical interactions of phenolic moieties to overcome such limitations in bone tissue engineering efforts. Highly osteoconductive hybrid hydrogel patches were fabricated by incorporating inorganic minerals, hydroxyapatite (HAP), or whitlockite (WKT), into pyrogallol-conjugated hyaluronic acid (HA-PG). The hybrid HA-PG patches exhibited improved mechanical strength and reinforced structural/physical properties owing to additional intermolecular complexation between oxidized PG moieties and ions released from inorganic particles. The sustained release of bone morphogenetic protein-2 (BMP-2) from hybrid patches was prolonged by combination of the inherent nucleophilic affinity of oxidized PG and electrostatic interactions between inorganic particles and BMP-2. With increased osteoconductivity, hybrid patches with HAP or WKT enhanced the osteogenic differentiation of human stem cells while also promoting new bone formation in a critical-sized calvarial defect. Our study demonstrates a translational potential of phenolic adhesive hydrogels engineered with inorganic minerals for orthopedic applications.
10.1016/j.jconrel.2020.09.006
Instructive nanofibrous scaffold comprising runt-related transcription factor 2 gene delivery for bone tissue engineering.
Monteiro Nelson,Ribeiro Diana,Martins Albino,Faria Susana,Fonseca Nuno A,Moreira João N,Reis Rui L,Neves Nuno M
ACS nano
Inducer molecules capable of regulating mesenchymal stem cell differentiation into specific lineages have proven effective in basic science and in preclinical studies. Runt-related transcription factor 2 (RUNX2) is considered to be the central gene involved in the osteoblast phenotype induction, which may be advantageous for inducing bone tissue regeneration. This work envisions the development of a platform for gene delivery, combining liposomes as gene delivery devices, with electrospun nanofiber mesh (NFM) as a tissue engineering scaffold. pDNA-loaded liposomes were immobilized at the surface of functionalized polycaprolactone (PCL) NFM. Human bone-marrow-derived mesenchymal stem cells (hBMSCs) cultured on RUNX2-loaded liposomes immobilized at the surface of electrospun PCL NFM showed enhanced levels of metabolic activity and total protein synthesis. RUNX2-loaded liposomes immobilized at the surface of electrospun PCL NFMs induce a long-term gene expression of eGFP and RUNX2 by cultured hBMSCs. Furthermore, osteogenic differentiation of hBMSCs was also achieved by the overexpression of other osteogenic markers in medium free of osteogenic supplementation. These findings demonstrate that surface immobilization of RUNX2 plasmid onto elestrospun PCL NFM can produce long-term gene expression in vitro, which may be employed to enhance the osteoinductive properties of scaffolds used for bone tissue engineering strategies.
10.1021/nn5021049
Multicellularity-interweaved bone regeneration of BMP-2-loaded scaffold with orchestrated kinetics of resorption and osteogenesis.
Niu Haoyi,Ma Yifan,Wu Guangyu,Duan Bing,Wang Ying,Yuan Yuan,Liu Changsheng
Biomaterials
Synchronization of material resorption and new bone formation is vital to achieve harmonious bone regeneration in the treatment of large bone defects. To exposit the resorption/osteogenesis properties in the guided bone repairing, rhBMP-2-loaded trimodal macro/micro/nano-porous bioactive glass scaffolds (TMS-rhBMP-2) were set as substrate model. We penetratingly investigated the particular function of hierarchical structure and incorporated rhBMP-2 in the resorption/osteogenesis, and dissected the cellular interplay throughout the regenerative procedure. The results suggested that rhBMP-2 significantly facilitated osteoclastogenesis-mediated scaffold degradation and strikingly up-regulated mesenchymal stem cells (MSCs)-involved osteogenesis in vitro. Further gene microarray and related proteins expression indicated that in the presence of rhBMP-2, MSCs rather than differentiated MSCs could exert synergistic effects on osteoclastogenesis, osteoclasts maturation and resorptive function; meanwhile, rhBMP-2-induced MSCs osteogenesis was also strengthened by the osteoclasts. In vivo micro-CT, X-ray, kinetic and histological analyses qualitatively and quantitively demonstrated the optimized coupling of bioresorption/osteogenesis and the most rapid regeneration in TMS-rhBMP-2. Consequently, with rhBMP-2 acted as ignitor and MSCs/osteoclasts interaction as booster, a harmonious bone regeneration was obtained. Besides, long-term magnetic resonance imaging (MRI) in virtue of Gd suggested that the degradation products mainly distributed in liver and spleen, verifying the accumulation/discharge profiles and safety application of TMS-rhBMP-2 system in vivo. This study will not merely provide guidance for the design of clinical bone repairing materials, but shed substantial light on the multicell-mediated tissue regeneration.
10.1016/j.biomaterials.2019.05.027
Unidirectional gene delivery electrospun fibrous membrane via charge repulsion for tendon repair.
Bioactive materials
Gene therapy is capable of efficiently regulating the expression of abnormal genes in diseased tissues and expected to be a therapeutic option for refractory diseases. However, unidirectional targeting gene therapy is always desired at the tissue interface. In this study, inspired by the principle that like charges repulse each other, a positively charged micro-nano electrospun fibrous membrane with dual-layer structure was developed by electrospinning technology to achieve unidirectional delivery of siRNA-loaded cationic nanocarriers, thus realizing unidirectional gene therapy at the tendon-paratenon interface. Under the charge repulsion of positively charged layer, more cationic COX-2 siRNA nanocarriers were enriched in peritendinous tissue, which not only improved the bioavailability of the gene drug to prevent the peritendinous adhesion formation, but also avoided adverse effects on the fragile endogenous healing of tendon itself. In summary, this study provides an innovative strategy for unidirectional targeting gene therapy of tissue interface diseases by utilizing charge repulsion to facilitate unidirectional delivery of gene drugs.
10.1016/j.bioactmat.2024.03.008
Three dimensional cell printing with sulfated alginate for improved bone morphogenetic protein-2 delivery and osteogenesis in bone tissue engineering.
Park Jisun,Lee Su Jeong,Lee Hwangjae,Park Su A,Lee Jae Young
Carbohydrate polymers
Three-dimensional (3D) cell printing is a unique technique that enables free-form fabrication of cell-laden hydrogel scaffolds with controllable features and interconnected pores for tissue engineering applications. To this end, bioink materials able to offer good printability and favorable cellular interaction are highly required. Herein, we synthesized alginate sulfate, which is a structural mimic of heparin that can strongly bind with growth factors to prolong their activities, and studied its feasibility for cell printing applications. Several bio-inks composed of alginate and alginate-sulfate were studied to characterize their material properties and their utilities in 3D printing. The inclusion of alginate-sulfate in bio-inks (alginate/alginate-sulfate) did not significantly influence their rheological properties and allowed for a good 3D printing processibility with distinct pores and features. Moreover, alginate/alginate-sulfate bio-inks exhibited an improved retention of bone morphogenetic protein 2 in 3D-printed scaffolds. Osteoblastic proliferation and differentiation in vitro were promoted by alginate/alginate-sulfate 3D-printed constructs with an optimal composition of 3% alginate and 2% alginate-sulfate. We envision that bio-inks displaying prolonged interactions with growth factors will be useful for tissue engineering applications including bone regeneration.
10.1016/j.carbpol.2018.05.048
Bone regeneration through controlled release of bone morphogenetic protein-2 from 3-D tissue engineered nano-scaffold.
Journal of controlled release : official journal of the Controlled Release Society
The objective of the present study was to enhance ectopic bone formation through the controlled release of bone morphogenetic protein-2 (BMP-2) from an injectable three dimensional (3-D) tissue engineered nano-scaffold. We demonstrate that a 3-D scaffold can be formed by mixing of peptide-amphiphile (PA) aqueous solution with BMP-2 suspension. A 3-D network of nanofibers was formed by mixing BMP-2 suspensions with dilute aqueous solutions of PA. Scanning electron microscopy (SEM) observation revealed the formation of fibrous assemblies with an extremely high aspect ratio and high surface areas. In vivo release profile of BMP-2 from 3-D network of nanofibers was investigated. In addition, ectopic bone formation induced by the released BMP-2 was assessed in a rat model using histological and biochemical examinations. It was demonstrated that the injection of an aqueous solution of PA together with BMP-2 into the back subcutis of rats, resulted in the formation of a transparent 3-D hydrogel at the injected site and induced significant homogeneous ectopic bone formation around the injected site, in marked contrast to BMP-2 injection alone or PA injection alone. The combination of BMP-2-induced bone formation is a promising procedure to improve tissue regeneration.
10.1016/j.jconrel.2006.11.018
Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration.
Tian Haijun,Du Juanjuan,Wen Jing,Liu Yang,Montgomery Scott R,Scott Trevor P,Aghdasi Bayan,Xiong Chengjie,Suzuki Akinobu,Hayashi Tetsuo,Ruangchainikom Monchai,Phan Kevin,Weintraub Gil,Raed Alobaidaan,Murray Samuel S,Daubs Michael D,Yang Xianjin,Yuan Xu-Bo,Wang Jeffrey C,Lu Yunfeng
ACS nano
Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth-factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules.
10.1021/acsnano.5b07950
Osteoblast-Targeting-Peptide Modified Nanoparticle for siRNA/microRNA Delivery.
Sun Yao,Ye Xiongzhen,Cai Mingxiang,Liu Xiangning,Xiao Jia,Zhang Chenyang,Wang Yayu,Yang Li,Liu Jiafan,Li Shannai,Kang Chen,Zhang Bin,Zhang Qi,Wang Zuolin,Hong An,Wang Xiaogang
ACS nano
Antiosteoporosis gene-based drug development strategies are presently focused on targeting osteoblasts to either suppress bone loss or increase bone mass. Although siRNA/microRNA-based gene therapy has enormous potential, it is severely limited by the lack of specific cell-targeting delivery systems. We report an osteoblast-targeting peptide (SDSSD) that selectively binds to osteoblasts via periostin. We developed SDSSD-modified polyurethane (PU) nanomicelles encapsulating siRNA/microRNA that delivers drugs to osteoblasts; the data showed that SDSSD-PU could selectively target not only bone-formation surfaces but also osteoblasts without overt toxicity or eliciting an immune response in vivo. We used the SDSSD-PU delivery system to deliver anti-miR-214 to osteoblasts and our results showed increased bone formation, improved bone microarchitecture, and increased bone mass in an ovariectomized osteoporosis mouse model. SDSSD-PU may be a useful osteoblast-targeting small nucleic acid delivery system that could be used as an anabolic strategy to treat osteoblast-induced bone diseases.
10.1021/acsnano.5b07828
Harnessing anti-inflammatory pathways and macrophage nano delivery to treat inflammatory and fibrotic disorders.
Advanced drug delivery reviews
Targeting specific organs and cell types using nanotechnology and sophisticated delivery methods has been at the forefront of applicative biomedical sciences lately. Macrophages are an appealing target for immunomodulation by nanodelivery as they are heavily involved in various aspects of many diseases and are highly plastic in their nature. Their continuum of functional "polarization" states has been a research focus for many years yielding a profound understanding of various aspects of these cells. The ability of monocyte-derived macrophages to metamorphose from pro-inflammatory to reparative and consequently to pro-resolving effectors has raised significant interest in its therapeutic potential. Here, we briefly survey macrophages' ontogeny and various polarization phenotypes, highlighting their function in the inflammation-resolution shift. We review their inducing mediators, signaling pathways, and biological programs with emphasis on the nucleic acid sensing-IFN-I axis. We also portray the polarization spectrum of macrophages and the characteristics of their transition between different subtypes. Finally, we highlighted different current drug delivery methods for targeting macrophages with emphasis on nanotargeting that might lead to breakthroughs in the treatment of wound healing, bone regeneration, autoimmune, and fibrotic diseases.
10.1016/j.addr.2024.115204
Tuning physical properties and BMP-2 release rates of injectable hydrogel systems for an optimal bone regeneration effect.
Seo Bo-Bae,Koh Jeong-Tae,Song Soo-Chang
Biomaterials
For a substance to be used as a drug delivery carrier and tissue inducible material for a target disease, its drug release rate and physical properties should be optimized to facilitate the healing process. We developed multi-tunable hydrogel systems with various physical properties and release behaviors to determine the optimal conditions for bone regeneration. Five injectable poly(phosphazene) hydrogels were developed with different types and amounts of anionic side-chains. The five polymer hydrogels showed considerably different in vitro and in vivo performances for sol-gel phase transition, dissolution/degradation, water uptake, and pore size. Furthermore, bone morphogenetic protein-2 (BMP-2) was loaded into the polymer hydrogels by forming nano-sized ionic-complexes with each polymer. The five types of nanocomplex hydrogels showed completely different BMP-2 release rates. By administering each nanocomplex hydrogel to mouse calvarial, we identified the most adapted nanocomplex hydrogel system for effective bone regeneration. The BMP-2 release rate was the most important factor in effective bone regeneration. Finally, the bone regeneration effect of the optimized hydrogel system was investigated in a critical-sized calvarial defect model.
10.1016/j.biomaterials.2017.01.016
A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche.
ACS nano
Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.
10.1021/acsnano.3c03828
Autologous liquid platelet rich fibrin: A novel drug delivery system.
Miron Richard J,Zhang Yufeng
Acta biomaterialia
There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. Substantial work to date has focused on the potential role of these biomolecules during the healing process, and the carrier system utilized is a key factor in their effectiveness. Platelet rich fibrin (PRF) is a naturally derived fibrin scaffold that is easily obtained from peripheral blood following centrifugation. Slower centrifugation speeds have led to the commercialization of a liquid formulation (liquid-PRF) resulting in an upper plasma layer composed of liquid fibrinogen/thrombin prior to clot formation that remains in its liquid phase for approximately 15 min until injected into bodily tissues. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules. Potential target molecules including large (growth factors/cytokines and morphogenetic/angiogenic factors), as well as small (antibiotics, peptides, gene therapy and anti-osteoporotic) molecules are considered potential candidates for enhanced bone/cartilage tissue regeneration. Furthermore, liquid-PRF is introduced as a potential carrier system for various cell types and nano-sized particles that are capable of limiting/by-passing the immune system and minimizing potential foreign body reactions within host tissues following injection. STATEMENT OF SIGNIFICANCE:There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. This review article focuses on the use of a liquid version of platelet rich fibrin (PRF) composed of liquid fibrinogen/thrombin as a drug delivery system. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules including growth factors, cytokines and morphogenetic/angiogenic factors, as well as antibiotics, peptides, gene therapy and anti-osteoporotic molecules as potential candidates for enhanced bone/cartilage tissue regeneration.
10.1016/j.actbio.2018.05.021
Bone-Targeting Exosome Mimetics Engineered by Bioorthogonal Surface Functionalization for Bone Tissue Engineering.
Nano letters
Extracellular vesicles have received a great interest as safe biocarriers in biomedical engineering. There is a need to develop more efficient delivery strategies to improve localized therapeutic efficacy and minimize off-target adverse effects. Here, exosome mimetics (EMs) are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered EMs is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. The EM-bound construct provided a biocompatible substrate for cell adhesion, proliferation, and osteogenic differentiation. Particularly, the incorporation of Smoothened agonist (SAG) into EMs greatly increased the osteogenic capacity through the activation of hedgehog signaling. Furthermore, the scaffold integrated with EM/SAG significantly improved in vivo reossification. Lastly, biodistribution studies confirmed the accumulation of systemically administered EMs in bone tissue. This facile engineering strategy could be a versatile tool to promote bone regeneration, offering a promising nanomedicine approach to the sophisticated treatment of bone diseases.
10.1021/acs.nanolett.2c04159
Biomimetic anti-inflammatory nano-capsule serves as a cytokine blocker and M2 polarization inducer for bone tissue repair.
Yin Chengcheng,Zhao Qin,Li Wu,Zhao Zifan,Wang Jinyang,Deng Tian,Zhang Peng,Shen Kailun,Li Zubing,Zhang Yufeng
Acta biomaterialia
Controlling of pro-inflammation induced by pro-inflammatory cytokines and anti-inflammatory response induced by M2 macrophages is important for osteogenesis in the process of bone tissue repair. Thus, we fabricated biomimetic anti-inflammatory nano-capsule (BANC) that can block cytokines and promote M2 macrophage polarization, presenting a positive role for bone tissue repair. The BANC is a biomimic nanosystem, coated with lipopolysaccharide-treated macrophage cell membranes with cytokine receptors enveloping gold nanocage (AuNC) as "cytokine blocker", and loaded with resolvin D1 inside into AuNC as "M2 polarization inducer" whose controlled-release could be triggered under near-infrared laser irradiation in sequence, and these chronological events were consistent with the healing process of bone tissue repair. Moreover, in vivo application of femoral bone defects revealed that the BANC composite boron-containing mesoporous bioactive glass scaffolds improved the final effects of bone tissue repair through preventing inflammatory response, promoting M2 polarization in sequence in accord with the in vitro investigation. Hence, cytokine neutralization and M2 macrophage polarization enables the BANC to enhance the bone tissue repair as a biomimetic anti-inflammation effector. Therefore, this study provides potential therapeutic strategies for trauma-mediated or inflammation-related bone defects based on a biomimetic nanomaterial with weakened pro-inflammatory and enhanced anti-inflammatory effects. STATEMENT OF SIGNIFICANCE: Cell membrane-mimic nanomaterials have been popular for blocking natural cell responses for some infection diseases, yet their role in biological process of bone repair is unknown. Here, we fabricated Biomimetic Anti-inflammatory Nano-Capsule (BANC), coated with cell membrane with cytokines receptors on the surface which could neutralize the pro-inflammatory cytokine receptor to block activated pro-inflammation, loaded with Resolvin D1 inside which could be controllably released by NIR irradiation to promote M2 macrophage polarization for the following bone formation during the process of bone repair. Administration of BANC as cytokines blocker and M2 polarization inducer to enhance the bone regeneration, thus presenting a promising potential for the treatment of bone repair and regeneration.
10.1016/j.actbio.2019.11.025
Injectable polysaccharide hydrogel embedded with hydroxyapatite and calcium carbonate for drug delivery and bone tissue engineering.
Ren Bowen,Chen Xueyun,Du Shoukang,Ma Ye,Chen Huinan,Yuan Guoliang,Li Jianliang,Xiong Dangsheng,Tan Huaping,Ling Zhonghua,Chen Yong,Hu Xiaohong,Niu Xiaohong
International journal of biological macromolecules
To meet the progressive requirements for bone regeneration purpose, injectable hydrogels have attracted increasing attention in tissue regeneration and local drug delivery applications. In this study, we report a facile method to prepare injectable and degradable polysaccharide-based hydrogels doubly integrated with hydroxyapatite (HAp) nanoparticles and calcium carbonate microspheres (CMs) under physiological condition. The mechanism of cross-linking is attributed to the Schiff-base reaction between amino and aldehyde groups of carboxymethyl chitosan (CMCS) and oxidized alginate (OAlg), respectively. Synchronously, tetracycline hydrochloride (TH) loaded CMs were fabricated by the precipitation reaction with an average diameter of 6.62 μm. To enhance bioactive and mechanical properties, nano-HAp and CMs containing TH were encapsulated into the polysaccharide-based hydrogel to form injectable gel scaffolds for imitation of bone niche. The gelation time, morphology, mechanical properties, swelling ratio and in vitro degradation of the gel scaffolds could be controlled by varying HAp and CMs contents. Moreover, the composite gel scaffolds had good sustained drug release and antibacterial properties, as confirmed by drugs release calculation and antibacterial evaluation. In addition, the gel scaffolds were found to be self-healing due to dynamic equilibrium of the Schiff-base linkages. These results suggested that the prepared composite gel scaffolds hold great potential for drug delivery and regeneration of irregular bone defects.
10.1016/j.ijbiomac.2018.06.200
Bioinspired trimodal macro/micro/nano-porous scaffolds loading rhBMP-2 for complete regeneration of critical size bone defect.
Tang Wei,Lin Dan,Yu Yuanman,Niu Haoyi,Guo Han,Yuan Yuan,Liu Changsheng
Acta biomaterialia
Critical size bone defects raise great demands for efficient bone substitutes. Mimicking the hierarchical porous architecture and specific biological cues of natural bone has been considered as an effective strategy to facilitate bone regeneration. Herein, a trimodal macro/micro/nano-porous scaffold loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) was developed. With mesoporous bioactive glass (MBG) as matrix, a trimodal MBG scaffold (TMS) with enhanced compressive strength (4.28 MPa, porosity of 80%) was prepared by a "viscosity controlling" and "homogeneous particle reinforcing" multi-template process. A 7.5 nm, 3D cubic (Im3m) mesoporous structure was tailored for a "size-matched entrapment" of rhBMP-2 to achieve sustained release and preserved bioactivity. RhBMP-2-loaded TMS (TMS/rhBMP-2) induced excellent cell attachment, ingrowth and osteogenesis in vitro. Further in vivo ectopic bone formation and orthotopic rabbit radius critical size defect results indicated that compared to the rhBMP-2-loaded bimodal macro/micro- and macro/nano-porous scaffolds, TMS/rhBMP-2 exhibited appealing bone regeneration capacity. Particularly, in critical size defect, complete bone reconstruction with rapid medullary cavity reunion and sclerotin maturity was observed on TMS/rhBMP-2. On the basis of these results, TMS/rhBMP-2 developed here represents a promising bone substitute for clinical application and the concepts proposed in this study might provide new thoughts on development of future orthopedic biomaterials. STATEMENT OF SIGNIFICANCE:Limited self-regenerating capacity of human body makes the reconstruction of critical size bone defect a significant challenge. Current bone substitutes often exhibit undesirable therapeutic efficacy due to poor osteoconductivity or low osteoinductivity. Herein, TMS/rhBMP-2, an advanced mesoporous bioactive glass (MBG) scaffold with osteoconductive trimodal macro/micro/nano-porosity and osteoinductive rhBMP-2 delivery was developed. The preparative and mechanical problems of hierarchical MBG scaffold were solved without affecting its excellent biocompatibilities, and rhBMP-2 immobilization in sizematched mesopores was first explored. Combining structural and biological cues, TMS/rhBMP-2 achieved a complete regeneration with rapid medullary cavity reunion and sclerotin maturity in rabbit radius critical size defects. The design conceptions proposed in this study might provide new thoughts on development of future orthopedic biomaterials.
10.1016/j.actbio.2015.12.006
Controlled Co-delivery of Growth Factors through Layer-by-Layer Assembly of Core-Shell Nanofibers for Improving Bone Regeneration.
Cheng Gu,Yin Chengcheng,Tu Hu,Jiang Shan,Wang Qun,Zhou Xue,Xing Xin,Xie Congyong,Shi Xiaowen,Du Yuming,Deng Hongbing,Li Zubing
ACS nano
The regeneration of bone tissue is regulated by both osteogenic and angiogenic growth factors which are expressed in a coordinated cascade of events. The aim of this study was to create a dual growth factor-release system that allows for time-controlled release to facilitate bone regeneration. We fabricated core-shell SF/PCL/PVA nanofibrous mats using coaxial electrospinning and layer-by-layer (LBL) techniques, where bone morphogenetic protein 2 (BMP2) was incorporated into the core of the nanofibers and connective tissue growth factor (CTGF) was attached onto the surface. Our study confirmed the sustained release of BMP2 and a rapid release of CTGF. Both in vitro and in vivo experiments demonstrated improvements in bone tissue recovery with the dual-drug release system. In vivo studies showed improvement in bone regeneration by 43% compared with single BMP2 release systems. Time-controlled release enabled by the core-shell nanofiber assembly provides a promising strategy to facilitate bone healing.
10.1021/acsnano.8b06032
Intra-articular delivery of kartogenin-conjugated chitosan nano/microparticles for cartilage regeneration.
Kang Mi Lan,Ko Ji-Yun,Kim Ji Eun,Im Gun-Il
Biomaterials
We developed an intra-articular (IA) drug delivery system to treat osteoarthritis (OA) that consisted of kartogenin conjugated chitosan (CHI-KGN). Kartogenin, which promotes the selective differentiation of mesenchymal stem cells (MSCs) into chondrocytes, was conjugated with low-molecular-weight chitosan (LMWCS) and medium-molecular-weight chitosan (MMWCS) by covalent coupling of kartogenin to each chitosan using an ethyl(dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) catalyst. Nanoparticles (NPs, 150 ± 39 nm) or microparticles (MPs, 1.8 ± 0.54 μm) were fabricated from kartogenin conjugated-LMWCS and -MMWCS, respectively, by an ionic gelation using tripolyphosphate (TPP). The in vitro release profiles of kartogenin from the particles showed sustained release for 7 weeks. When the effects of the CHI-KGN NPs or CHI-KGN MPs were evaluated on the in vitro chondrogenic differentiation of human bone marrow MSCs (hBMMSCs), the CHI-KGN NPs and CHI-KGN MPs induced higher expression of chondrogenic markers from cultured hBMMSCs than unconjugated kartogenin. In particular, hBMMSCs treated with CHI-KGN NPs exhibited more distinct chondrogenic properties in the long-term pellet cultures than those treated with CHI-KGN MPs. The in vivo therapeutic effects of CHI-KGN NPs or CHI-KGN MPs were investigated using a surgically-induced OA model in rats. The CHI-KGN MPs showed longer retention time in the knee joint than the CHI-KGN NPs after IA injection in OA rats. The rats treated with CHI-KGN NPs or CHI-KGN MPs by IA injection showed much less degenerative changes than untreated control or rats treated with unconjugated kartogenin. In conclusion, CHI-KGN NPs or CHI-KGN MPs can be useful polymer-drug conjugates as an IA drug delivery system to treat OA.
10.1016/j.biomaterials.2014.08.042
Scaffolds for bone regeneration made of hydroxyapatite microspheres in a collagen matrix.
Cholas Rahmatullah,Kunjalukkal Padmanabhan Sanosh,Gervaso Francesca,Udayan Gayatri,Monaco Graziana,Sannino Alessandro,Licciulli Antonio
Materials science & engineering. C, Materials for biological applications
Biomimetic scaffolds with a structural and chemical composition similar to native bone tissue may be promising for bone tissue regeneration. In the present work hydroxyapatite mesoporous microspheres (mHA) were incorporated into collagen scaffolds containing an ordered interconnected macroporosity. The mHA were obtained by spray drying of a nano hydroxyapatite slurry prepared by the precipitation technique. X-ray diffraction (XRD) analysis revealed that the microspheres were composed only of hydroxyapatite (HA) phase, and energy-dispersive x-ray spectroscopy (EDS) analysis revealed the Ca/P ratio to be 1.69 which is near the value for pure HA. The obtained microspheres had an average diameter of 6 μm, a specific surface area of 40 m(2)/g as measured by Brunauer-Emmett-Teller (BET) analysis, and Barrett-Joyner-Halenda (BJH) analysis showed a mesoporous structure with an average pore diameter of 16 nm. Collagen/HA-microsphere (Col/mHA) composite scaffolds were prepared by freeze-drying followed by dehydrothermal crosslinking. SEM observations of Col/mHA scaffolds revealed HA microspheres embedded within a porous collagen matrix with a pore size ranging from a few microns up to 200 μm, which was also confirmed by histological staining of sections of paraffin embedded scaffolds. The compressive modulus of the composite scaffold at low and high strain values was 1.7 and 2.8 times, respectively, that of pure collagen scaffolds. Cell proliferation measured by the MTT assay showed more than a 3-fold increase in cell number within the scaffolds after 15 days of culture for both pure collagen scaffolds and Col/mHA composite scaffolds. Attractive properties of this composite scaffold include the potential to load the microspheres for drug delivery and the controllability of the pore structure at various length scales.
10.1016/j.msec.2016.03.022
Multifunctional MXene-Based Bioactive Materials for Integrated Regeneration Therapy.
ACS nano
The reconstruction engineering of tissue defects accompanied by major diseases including cancer, infection, and inflammation is one of the important challenges in clinical medicine. The development of innovative tissue engineering strategies such as multifunctional bioactive materials presents a great potential to overcome the challenge of disease-impaired tissue regeneration. As the major representative of two-dimensional nanomaterials, MXenes have shown multifunctional physicochemical properties and have been diffusely studied as multimodal nanoplatforms in the field of biomedicine. This review summarized the recent advances in the multifunctional properties of MXenes and integrated regeneration-therapy applications of MXene-based biomaterials, including tissue regeneration-tumor therapy, tissue regeneration-infection therapy, and tissue regeneration-inflammation therapy. MXenes have been recognized as good candidates for promoting tissue regeneration and treating diseases through photothermal therapy, regulating cell behavior, and drug and gene delivery. The current challenges and future perspectives of MXene-based biomaterials in integrated regeneration-therapy are also discussed well in this review. In summary, MXene-based biomaterials have shown promising potential for integrated tissue regeneration and disease treatment due to their favorable physicochemical properties and bioactive functions. However, there are still many obstacles and challenges that must be addressed for the regeneration-therapy applications of MXene-based biomaterials, including understanding the bioactive mechanism, ensuring long-term biosafety, and improving their targeting therapy capacity.
10.1021/acsnano.3c01913
Non-mulberry silk fibroin grafted poly (Є-caprolactone)/nano hydroxyapatite nanofibrous scaffold for dual growth factor delivery to promote bone regeneration.
Bhattacharjee Promita,Naskar Deboki,Maiti Tapas K,Bhattacharya Debasis,Kundu Subhas C
Journal of colloid and interface science
HYPOTHESIS:This study aims at developing biodegradable, mineralized, nanofibrous scaffolds for use in bone regeneration. Scaffolds are loaded with combinations of bone morphogenic protein-2 (rhBMP-2) and transforming growth factor beta (TGF-β) and evaluated in vitro for enhancement in osteoinductivity. EXPERIMENTS:Poly(Є-caprolactone) (PCL) doped with different portions of nano-hydroxyapatite is electrospun into nanofibrous scaffolds. Non-mulberry silk fibroin (NSF) obtained from Antheraea mylitta is grafted by aminolysis onto them. Scaffolds prepared have three concentrations of nano-hydroxyapatite: 0% (NSF-PCL), 25% (NSF-PCL/n25), and 50% (NSF-PCL/n50). Growth factor loading is carried out in three different combinations, solely rhBMP-2 (BN25), solely TGF-β (TN25) and rhBMP-2+TGF-β (T/B N25) via carbodiimide coupling. FINDINGS:NSF-PCL/n25 showed the best results in examination of mechanical properties, bioactivity, and cell viability. Hence only NSF-PCL/n25 is selected for loading growth factors and subsequent detailed in vitro experiments using MG-63 cell-line. Both growth factors show sustain release kinetics from the matrix. The T/B N25 scaffolds support cellular activity, proliferation, and triggering of bone-associated genes' expression better and promote earlier cell differentiation. Dual growth factor loaded NSF grafted electrospun PCL/nHAp scaffolds show promise for further development into a suitable scaffold for bone tissue engineering.
10.1016/j.jcis.2016.03.020
Pinecone-Inspired Nanoarchitectured Smart Microcages Enable Nano/Microparticle Drug Delivery.
Advanced functional materials
Drug delivery plays a vital role in medicine and health, but the on-demand delivery of large-sized drugs using stimuli-triggered carriers is extremely challenging. Most present capsules consist of polymeric dense shells with nanosized pores (<10 nm), thus typically lack permeability for nano/microparticle drugs. Here, a pinecone-inspired smart microcage with open network shells, assembled from cellulose nanofibrils (CNFs), is reported for nano/microparticle drug delivery. The approach allows the nanoarchitectured, functionalized CNFs to assemble into mechanically robust, haystack-like network shells with tunable large-through pores and polypeptide-anchored points on a large scale. Such open network shells can intelligently open/close triggered by lesion stimuli, making the therapy "always on-demand." The resulting pinecone-inspired microcages exhibit integrated properties of superior structural stability, superhydrophilicity, and pH-triggered, smart across-shell transport of emerging antimicrobial silver nanoparticles and bioactive silicate nanoplatelets (sizes of >100 nm), which enable both extraordinary anti-infection and bone regeneration. This work provides new insights into the design and development of multifunctional encapsulation and delivery carriers for medical and environmental applications.
10.1002/adfm.202002434
Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering.
Yao Qingqing,Liu Yangxi,Selvaratnam Balaranjan,Koodali Ranjit T,Sun Hongli
Journal of controlled release : official journal of the Controlled Release Society
Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering.
10.1016/j.jconrel.2018.04.011
Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.
Journal of nanobiotechnology
BACKGROUND:Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS:In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION:In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.
10.1186/s12951-024-02352-4
Nanogels for regenerative medicine.
Grimaudo Maria Aurora,Concheiro Angel,Alvarez-Lorenzo Carmen
Journal of controlled release : official journal of the Controlled Release Society
Nanogels have been widely explored for drug delivery, but their applications in the tissue engineering field are still quite recent. Regenerative medicine also demands controlled delivery of growth factors and other active substances able to promote cell adhesion and guide cell differentiation and tissue formation. Moreover, nanogels could be added to tissue scaffolds for modifying their inner architecture, texture and mechanical properties, which are critical for regulating cell behavior. This review aims to provide an insight into the different roles that nanogels may play for improving tissue regeneration. Last decade literature has been carefully analyzed with a focus on in vivo outcomes. After an introductory section to nanogels, relevant examples of their performance for skin and bone tissue regeneration applications are discussed. Healing of chronic wounds and critical size bone fractures may significantly improve thanks to the use of nanogels solely or in combination with scaffolds. Nanogel roles in regenerating vessels, cardiac tissue, urothelium and urethral muscle tissue are also presented. Overall, the information gathered in the review clearly highlights the relevance of multidisciplinary approaches to design nanogels that can face up to the needs of the regenerative medicine. Nanogels may help bring together researchers working in active ingredient formulation, controlled release, nanomechanics, tissue engineering and scaffolding with the common purpose of developing clinically relevant tools for the complete regeneration of complex tissues.
10.1016/j.jconrel.2019.09.015
Micro and nanotechnologies for bone regeneration: Recent advances and emerging designs.
Mohammadi Marzieh,Mousavi Shaegh Seyed Ali,Alibolandi Mona,Ebrahimzadeh Mohammad Hossein,Tamayol Ali,Jaafari Mahmoud Reza,Ramezani Mohammad
Journal of controlled release : official journal of the Controlled Release Society
Treatment of critical-size bone defects is a major medical challenge since neither the bone tissue can regenerate nor current regenerative approaches are effective. Emerging progresses in the field of nanotechnology have resulted in the development of new materials, scaffolds and drug delivery strategies to improve or restore the damaged tissues. The current article reviews promising nanomaterials and emerging micro/nano fabrication techniques for targeted delivery of biomolecules for bone tissue regeneration. In addition, recent advances in fabrication of bone graft substitutes with similar properties to normal tissue along with a brief summary of current commercialized bone grafts have been discussed.
10.1016/j.jconrel.2018.01.032
Modulation of Local Overactive Inflammation via Injectable Hydrogel Microspheres.
Bian Jiang,Cai Feng,Chen Hao,Tang Zhenzhou,Xi Kun,Tang Jincheng,Wu Liang,Xu Yichang,Deng Lianfu,Gu Yong,Cui Wenguo,Chen Liang
Nano letters
Although injectable hydrogel microsphere has demonstrated tremendous promise in clinical applications, local overactive inflammation in degenerative diseases could jeopardize biomaterial implantation's therapeutic efficacy. Herein, an injectable "peptide-cell-hydrogel" microsphere was constructed by covalently coupling of APETx2 and further loading of nucleus pulposus cells, which could inhibit local inflammatory cytokine storms to regulate the metabolic balance of ECM . The covalent coupling of APETx2 preserved the biocompatibility of the microspheres and achieved a controlled release of APETx2 for more than 28 days in an acidic environment. By delivering "peptide-cell-hydrogel" microspheres to a rat degenerative intervertebral disc at 4 weeks, the expression of ASIC-3 and IL-1β was significantly decreased for 3.53-fold and 7.29-fold, respectively. Also, the content of ECM was significantly recovered at 8 weeks. In summary, the proposed strategy provides an effective approach for tissue regeneration under overactive inflammatory responses.
10.1021/acs.nanolett.0c04713
Biotin-Avidin System-Based Delivery Enhances the Therapeutic Performance of MSC-Derived Exosomes.
ACS nano
Exosomes (EXs) shed by mesenchymal stem cells (MSCs) are potent therapeutic agents that promote wound healing and regeneration, but when used alone , their therapeutic potency is diminished by rapid clearance and bioactivity loss. Inspired by the biotin-avidin interaction, we developed a simple yet versatile method for the immobilization of MSC-derived EXs (MSC-EXs) into hydrogels and achieved sustained release for regenerative purposes. First, biotin-modified gelatin methacryloyl (Bio-GelMA) was fabricated by grafting NHS-PEG-biotin onto the amino groups of GelMA. Biotin-modified MSC-EXs (Bio-EXs) were then synthesized using an self-assembling biotinylation strategy, which provided sufficient binding sites for MSC-EX delivery with little effect on their cargo composition. Thereafter, Bio-EXs were immobilized in Bio-GelMA streptavidin to generate Bio-GelMA@Bio-EX hydrogels. An analysis demonstrated that Bio-EXs could be taken up by macrophages and exerted immunomodulatory effects similar to those of MSC-EXs, and Bio-GelMA@Bio-EX hydrogels provided sustained release of MSC-EXs for 7 days. After subcutaneous transplantation, a more constant retention of MSC-EXs in Bio-GelMA@Bio-EX hydrogels was observed for up to 28 days. When placed in an artificial periodontal multitissue defect, the functionalized hydrogels exhibited an optimized therapeutic performance to regrow complex periodontal tissues, including acellular cementum, periodontal ligaments (PDLs), and alveolar bone. In this context, Bio-GelMA@Bio-EX hydrogels exerted a robust immunomodulatory effect that promoted macrophage polarization toward an M2 phenotype. Our findings demonstrate that MSC-EXs delivered with the aid of the biotin-avidin system exhibit robust macrophage-modulating and repair-promoting functions and suggest a universal approach for the development of MSC-EX-functionalized biomaterials for advanced therapies.
10.1021/acsnano.3c00839
Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis-Osteogenesis Coupling for Promoting Vascularized Bone Regeneration.
ACS applied materials & interfaces
It has been confirmed that substantial vascularization is an effective strategy to heal large-scale bone defects in the field of bone tissue engineering. The local application of deferoxamine (DFO) is among the most common and effective methods for promoting the formation of blood vessels, although its short half-life in plasma, rapid clearance, and poor biocompatibility limit its therapeutic suitability. Herein, zeolitic imidazolate framework-8 (ZIF-8) was selected as a vehicle to extend the half-life of DFO. In the present study, a nano DFO-loaded ZIF-8 (DFO@ZIF-8) drug delivery system was established to promote angiogenesis-osteogenesis coupling. The nanoparticles were characterized, and their drug loading efficiency was examined to confirm the successful synthesis of nano DFO@ZIF-8. Additionally, due to the sustained release of DFO and Zn, DFO@ZIF-8 NPs were able to promote angiogenesis in human umbilical vein endothelial cells (HUVECs) culture and osteogenesis in bone marrow stem cells (BMSCs) in vitro. Furthermore, the DFO@ZIF-8 NPs promoted vascularization by enhancing the expression of type H vessels and a vascular network. The DFO@ZIF-8 NPs promoted bone regeneration in vivo by increasing the expression of OCN and BMP-2. RNA sequencing analysis revealed that the PI3K-AKT-MMP-2/9 and HIF-1α pathways were upregulated by DFO@ZIF-8 NPs in HUVECs, ultimately leading to the formation of new blood vessels. In addition, the mechanism by which DFO@ZIF-8 NPs promoted bone regeneration was potentially related to the synergistic effect of angiogenesis-osteogenesis coupling and Zn-mediation of the MAPK pathway. Taken together, DFO@ZIF-8 NPs, which were demonstrated to have low cytotoxicity and excellent coupling of angiogenesis and osteogenesis, represent a promising strategy for the reconstruction of critical-sized bone defects.
10.1021/acsami.2c23107
Acceleration of chondrogenic differentiation of human mesenchymal stem cells by sustained growth factor release in 3D graphene oxide incorporated hydrogels.
Shen He,Lin Hang,Sun Aaron X,Song Saijie,Wang Bing,Yang Yuanheng,Dai Jianwu,Tuan Rocky S
Acta biomaterialia
Damaged articular cartilage has limited self-healing capabilities, leading to degeneration that affects millions of people. Although cartilage tissue engineering is considered a promising approach for treatment, robust and long-term chondrogenesis within a 3-dimensional (3D) scaffold remains a major challenge for complete regeneration. Most current approaches involve incorporation of transforming growth factor-β (TGF-β) into the scaffold, but have limited utility owing to the short functional half-life and/or rapid clearance of TGF-β. In this study, we have tested the incorporation of graphene oxide nanosheets (GO) within a photopolymerizable poly-D, l-lactic acid/polyethylene glycol (PDLLA) hydrogel, for its applicability in sustained release of the chondroinductive growth factor TGF-β3. We found that with GO incorporation, the hydrogel scaffold (GO/PDLLA) exhibited enhanced initial mechanical strength, i.e., increased compressive modulus, and supported long-term, sustained release of TGF-β3 for up to 4 weeks. In addition, human bone marrow-derived mesenchymal stem cells (hBMSCs) seeded within TGF-β3 loaded GO/PDLLA hydrogels displayed high cell viability and improved chondrogenesis in a TGF-β3 concentration-dependent manner. hBMSCs cultured in GO/PDLLA also demonstrated significantly higher chondrogenic gene expression, including aggrecan, collagen type II and SOX9, and cartilage matrix production when compared to cultures maintained in GO-free scaffolds containing equivalent amounts of TGF-β3. Upon subcutaneous implantation in vivo, hBMSC-seeded TGF-β3-GO/PDLLA hydrogel constructs displayed considerably greater cartilage matrix than their TGF-β3/PDLLA counterparts without GO. Taken together, these findings support the potential application of GO in optimizing TGF-β3 induced hBMSC chondrogenesis for cartilage tissue engineering. STATEMENT OF SIGNIFICANCE: In this work, we have developed a graphene oxide (GO) incorporated, photocrosslinked PDLLA hybrid hydrogel for localized delivery and sustained release of loaded TGF-β3 to seeded cells. The incorporation of GO in PDLLA hydrogel suppressed the burst release of TGF-β3, and significantly prolonged the retention time of the TGF-β3 initially loaded in the hydrogel. Additionally, the GO improved the initial compressive strength of the hydrogel. Both in vitro analyses and in vivo implantation results showed that the GO/PDLLA constructs seeded with human mesenchymal stem cells (hMSCs) showed significantly higher cartilage formation, compared to GO-free scaffolds containing equivalent amount of TGF-β3. Findings from this work suggest the potential application of the GO-TGF/PDLLA hydrogel as a functional scaffold for hMSC-based cartilage tissue engineering.
10.1016/j.actbio.2020.01.048
Multi-layered PLLA-nanosheets loaded with FGF-2 induce robust bone regeneration with controlled release in critical-sized mouse femoral defects.
Murahashi Yasutaka,Yano Fumiko,Nakamoto Hideki,Maenohara Yuji,Iba Kousuke,Yamashita Toshihiko,Tanaka Sakae,Ishihara Kazuhiko,Okamura Yosuke,Moro Toru,Saito Taku
Acta biomaterialia
To overcome clinical issues caused by large bone defects and subsequent nonunion, various approaches to bone regeneration have been researched, including tissue engineering, biomaterials, stem cells and drug screening. Previously, we developed a free-standing biodegradable polymer nanosheet composed of poly(L-lactic acid) (PLLA) using a simple fabrication process consisting of spin-coating and peeling techniques. We reported that sandwich-type PLLA nanosheets loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) displayed long-lasting, sustained release of rhBMP-2, and markedly enhanced bone regeneration in mouse calvarial bone defects. Here, we fabricated multi-layered nanosheets loaded with fibroblast growth factor-2 (FGF-2), and investigated their application for long bone regeneration. Subcutaneously implanted tri-layered PLLA nanosheets displayed sustained release of loaded rhFGF-2 for about 2 weeks. Next, we prepared critical-sized mouse femoral defects and implanted mono- or tri-layered nanosheets, or a gelatin hydrogel with rhFGF-2. Amongst these conditions, the tri-layered nanosheet most efficiently induced bone regeneration. Indeed, bone regeneration was enhanced even after 4 weeks in the tri-layered nanosheet group, and was accompanied by FGFR1 activation and subsequent osteoblast differentiation. Multi-layered PLLA nanosheets loaded with rhFGF-2 may be useful for bone regenerative medicine. Furthermore, the multi-layered PLLA nanosheet structure may potentially be applied as a potent sustained-release carrier. STATEMENTS OF SIGNIFICANCE: Here, we describe multi-layered poly(L-lactic acid) (PLLA) nanosheets loaded with recombinant human fibroblast growth factor-2 (rhFGF-2) as a modified sustained-release carrier for bone regeneration. In vivo imaging system analysis revealed that subcutaneously implanted tri-layered PLLA nanosheets displayed sustained release of loaded rhFGF-2 for 2 weeks. In critical-sized mouse femoral defects, tri-layered nanosheets loaded with rhFGF-2 most efficiently induced bone regeneration. Notably, bone regeneration was enhanced even after 4 weeks in the tri-layered nanosheet group, and was accompanied by FGFR1 activation and subsequent osteoblast differentiation. Multi-layered PLLA nanosheets loaded with rhFGF-2 may be useful for bone regenerative medicine. Furthermore, the multi-layered PLLA nanosheet structure may potentially be applied as a potent sustained-release carrier.
10.1016/j.actbio.2018.12.031
Chitosan stabilizes platelet growth factors and modulates stem cell differentiation toward tissue regeneration.
Busilacchi Alberto,Gigante Antonio,Mattioli-Belmonte Monica,Manzotti Sandra,Muzzarelli Riccardo A A
Carbohydrate polymers
The idea of using chitosan as a functional delivery aid to support simultaneously PRP, stem cells and growth factors (GF) is associated with the intention to use morphogenic biomaterials to modulate the natural healing sequence in bone and other tissues. For example, chitosan-chondroitin sulfate loaded with platelet lysate was included in a poly(D,L-lactate) foam that was then seeded with human adipose-derived stem cells and cultured in vitro under osteogenic stimulus: the platelet lysate provided to the bone tissue the most suitable assortment of GF which induces the osteogenic differentiation of the mesenchymal stem cells. PDGF, FGF, IGF and TGF-β were protagonists in the repair of callus fractures. The release of GF from the composites of chitosan-PRP and either nano-hydroxyapatite or tricalcium phosphate was highly beneficial for enhancing MSC proliferation and differentiation, thus qualifying chitosan as an excellent vehicle. A number of biochemical characteristics of chitosan exert synergism with stem cells in the regeneration of soft tissues.
10.1016/j.carbpol.2013.06.044
Bone Regeneration from PLGA Micro-Nanoparticles.
Ortega-Oller Inmaculada,Padial-Molina Miguel,Galindo-Moreno Pablo,O'Valle Francisco,Jódar-Reyes Ana Belén,Peula-García Jose Manuel
BioMed research international
Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed.
10.1155/2015/415289
Enhanced bone regeneration using an insulin-loaded nano-hydroxyapatite/collagen/PLGA composite scaffold.
Wang Xing,Zhang Guilan,Qi Feng,Cheng Yongfeng,Lu Xuguang,Wang Lu,Zhao Jing,Zhao Bin
International journal of nanomedicine
Insulin is widely considered as a classical hormone and drug in maintaining energy and glucose homeostasis. Recently, insulin has been increasingly recognized as an indispensable factor for osteogenesis and bone turnover, but its applications in bone regeneration have been restricted because of the short periods of activity and uncontrolled release. In this study, we incorporated insulin-loaded poly lactic-co-glycolic-acid (PLGA) nanospheres into nano-hydroxyapatite/collagen (nHAC) scaffolds and investigated the bioactivity of the composite scaffolds in vitro and in vivo. Bioactive insulin was successfully released from the nanospheres within the scaffold, and the release kinetics of insulin could be efficiently controlled by uniform-sized nanospheres. The physical characterizations of the composite scaffolds demonstrated that incorporation of nanospheres in nHAC scaffolds using this method did not significantly change the porosity, pore diameters, and compressive strengths of nHAC. In vitro, the insulin-loaded nHAC/PLGA composite scaffolds possessed favorable biological function for bone marrow mesenchymal stem cells adhesion and proliferation, as well as the differentiation into osteoblasts. In vivo, the optimized bone regenerative capability of this composite scaffold was confirmed in rabbit mandible critical size defects. These results demonstrated successful development of a functional insulin-PLGA-nHAC composite scaffold that enhances the bone regeneration capability of nHAC.
10.2147/IJN.S150818
Multiscale patterned transplantable stem cell patches for bone tissue regeneration.
Kim Jangho,Bae Won-Gyu,Choung Han-Wool,Lim Ki Taek,Seonwoo Hoon,Jeong Hoon Eui,Suh Khap-Yang,Jeon Noo Li,Choung Pill-Hoon,Chung Jong Hoon
Biomaterials
Stem cell-based therapy has been proposed as an enabling alternative not only for the treatment of diseases but also for the regeneration of tissues beyond complex surgical treatments or tissue transplantation. In this study, we approached a conceptual platform that can integrate stem cells into a multiscale patterned substrate for bone regeneration. Inspired by human bone tissue, we developed hierarchically micro- and nanopatterned transplantable patches as synthetic extracellular matrices by employing capillary force lithography in combination with a surface micro-wrinkling method using a poly(lactic-co-glycolic acid) (PLGA) polymer. The multiscale patterned PLGA patches were highly flexible and showed higher tissue adhesion to the underlying tissue than did the single nanopatterned patches. In response to the anisotropically multiscale patterned topography, the adhesion and differentiation of human mesenchymal stem cells (hMSCs) were sensitively controlled. Furthermore, the stem cell patch composed of hMSCs and transplantable PLGA substrate promoted bone regeneration in vivo when both the micro- and nanotopography of the substrate surfaces were synergistically combined. Thus, our study concludes that multiscale patterned transplantable stem cell patches may have a great potential for bone regeneration as well as for various regenerative medicine approaches.
10.1016/j.biomaterials.2014.07.036
Sequential Dual-Biofactor Release from the Scaffold of Mesoporous HA Microspheres and PLGA Matrix for Boosting Endogenous Bone Regeneration.
Advanced healthcare materials
The combined design of scaffold structure and multi-biological factors is a prominent strategy to promote bone regeneration. Herein, a composite scaffold of mesoporous hydroxyapatite (HA) microspheres loaded with the bone morphogenetic protein-2 (BMP-2) and a poly(DL-lactic-co-glycolic acid) (PLGA) matrix is constructed by 3D printing. Furthermore, the chemokine stromal cell-derived factor-1α (SDF-1α) is adsorbed on a scaffold surface to achieve the sequential release of the dual-biofactors. The results indicate that the rapid release of SDF-1α chemokine on the scaffold surface effectively recruits bone marrow-derived mesenchymal stem cells (BMSCs) to the target defect area, whereas the long-term sustained release of BMP-2 from the HA microspheres in the degradable PLGA matrix successfully triggers the osteogenic differentiation in the recruited BMSCs, significantly promoting bone regeneration and reconstruction. In addition, these structures/biofactors specially combining scaffold exhibit significantly better biological performance than that of other combined scaffolds, including the bare HA/PLGA scaffold, the scaffold loaded with SDF-1α or BMP-2 biofactor alone, and the scaffold with surface SDF-1α and BMP-2 dual-biofactors. The utilization of mesoporous HA, the assembly method, and sequential release of the two biofactors in the 3D printed composite scaffold present a new method for future design of high-performance bone repairing scaffolds.
10.1002/adhm.202300624
Stimulation of bone regeneration following the controlled release of water-insoluble oxysterol from biodegradable hydrogel.
Hokugo Akishige,Saito Takashi,Li Andrew,Sato Keisuke,Tabata Yasuhiko,Jarrahy Reza
Biomaterials
Recently bone graft substitutes using bone morphogenetic proteins (BMPs) have been heralded as potential alternatives to traditional bone reconstruction procedures. BMP-based products, however, are associated with significant and potentially life-threatening side effects when used in the head and neck region and furthermore, are exorbitantly priced. Oxysterols, products of cholesterol oxidation, represent a class of molecules that are favorable alternatives or adjuncts to BMP therapy due to their low side effect profile and cost. In order to establish the optimal clinical utility of oxysterol, an optimal scaffold must be developed, one that allows the release of oxysterol in a sustained and efficient manner. In this study, we prepare a clinically applicable bone graft substitute engineered for the optimal release of oxysterol. We first solubilized oxysterol in water by making use of polymeric micelles using l-lactic acid oligomer (LAo) grafted gelatin. Then, the water-solubilized oxysterol was incorporated into a biodegradable hydrogel that was enzymatically degraded intracorporeally. In this manner, oxysterol could be released from the hydrogel in a degradation-driven manner. The water-solubilized oxysterol incorporated biodegradable hydrogel was implanted into rat calvarial defects and induced successful bone regeneration. The innovative significance of this study lies in the development of a bone graft substitute that couples the osteogenic activity of oxysterol with a scaffold designed for optimized oxysterol release kinetics, all of which lead to better repair of bone defects.
10.1016/j.biomaterials.2014.03.018
Electrospun highly porous poly(L-lactic acid)-dopamine-SiO fibrous membrane for bone regeneration.
Lu Zihan,Wang Weiguang,Zhang Jing,Bártolo Paulo,Gong Hugh,Li Jiashen
Materials science & engineering. C, Materials for biological applications
Electrospinning has been widely used to fabricate polymer fibrous scaffolds for bone tissue engineering because of their highly porous structures. In order to improve the biocompatibility of polymer scaffolds, some nano particles have been introduced into electrospun fibres. For example, silica nanoparticles (SiNPs), with high surface area and good biocompatibility, have been used for bone tissue engineering for better bone cell attachment. In this work, porous poly(L-lactic acid) (PLLA) fibrous membrane with high surface area was fabricated by electrospinning and post-treatment process. The membrane can serve as substrates of SiNPs for bone tissue engineering. Dopamine (DOP) was applied to modify the surface of PLLA fibres, which improved the coating strength of SiNPs on PLLA fibres. SiNP coating significantly improved the mechanical properties and hydrophilicity of PLLA/DOP/SiNP composite membranes. As a result of SiNPs coating, PLLA/DOP/SiNP membrane exhibited better cellular biocompatibility, more cell attachment and proliferation. These results demonstrate that porous PLLA/DOP/SiNP composite membrane with high surface area has high potential for periosteum in the field of bone regeneration applications.
10.1016/j.msec.2020.111359
Osteoporotic Bone Regeneration via Plenished Biomimetic PLGA Scaffold with Sequential Release System.
Small (Weinheim an der Bergstrasse, Germany)
Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.
10.1002/smll.202310734
Poly (glycerol sebacate) elastomer supports bone regeneration by its mechanical properties being closer to osteoid tissue rather than to mature bone.
Zaky S H,Lee K W,Gao J,Jensen A,Verdelis K,Wang Y,Almarza A J,Sfeir C
Acta biomaterialia
Mechanical load influences bone structure and mass. Arguing the importance of load-transduction, we investigated the mechanisms inducing bone formation using an elastomeric substrate. We characterized Poly (glycerol sebacate) (PGS) in vitro for its mechanical properties, compatibility with osteoprogenitor cells regarding adhesion, proliferation, differentiation under compression versus static cultures and in vivo for the regeneration of a rabbit ulna critical size defect. The load-transducing properties of PGS were compared in vitro to a stiffer poly lactic-co-glycolic-acid (PLA/PGA) scaffold of similar porosity and interconnectivity. Under cyclic compression for 7days, we report focal adhesion kinase overexpression on the less stiff PGS and upregulation of the transcription factor Runx2 and late osteogenic markers osteocalcin and bone sialoprotein (1.7, 4.0 and 10.0 folds increase respectively). Upon implanting PGS in the rabbit ulna defect, histology and micro-computed tomography analysis showed complete gap bridging with new bone by the PGS elastomer by 8weeks while minimal bone formation was seen in empty controls. Immunohistochemical analysis demonstrated the new bone to be primarily regenerated by recruited osteoprogenitors cells expressing periostin protein during early phase of maturation similar to physiological endochondral bone development. This study confirms PGS to be osteoconductive contributing to bone regeneration by recruiting host progenitor/stem cell populations and as a load-transducing substrate, transmits mechanical signals to the populated cells promoting differentiation and matrix maturation toward proper bone remodeling. We hence conclude that the material properties of PGS being closer to osteoid tissue rather than to mineralized bone, allows bone maturation on a substrate mechanically closer to where osteoprogenitor/stem cells differentiate to develop mature load-bearing bone. SIGNIFICANCE OF SIGNIFICANCE:The development of effective therapies for bone and craniofacial regeneration is a foremost clinical priority in the mineralized tissue engineering field. Currently at risk are patients seeking treatment for craniofacial diseases, traumas and disorders including birth defects such as cleft lip and palate, (1 in 525 to 714 live births), craniosynostosis (300-500 per 1,000,000 live births), injuries to the head and face (20 million ER visits per year), and devastating head and neck cancers (8000 deaths and over 30,000 new cases per year). In addition, approximately 6.2 million fractures occur annually in the United States, of which 5-10% fail to heal properly, due to delayed or non-union [1], and nearly half of adults aged 45-65 have moderate to advanced periodontitis with associated alveolar bone loss, which, if not reversed, will lead to the loss of approximately 6.5 teeth/individual [2]. The strategies currently available for bone loss treatment largely suffer from limitations in efficacy or feasibility, necessitating further development and material innovation. Contemporary materials systems themselves are indeed limited in their ability to facilitate mechanical stimuli and provide an appropriate microenvironment for the cells they are designed to support. We propose a strategy which aims to leverage biocompatibility, biodegradability and material elasticity in the creation of a cellular niche. Within this niche, cells are mechanically stimulated to produce their own extracellular matrix. The hypothesis that mechanical stimuli will enhance bone regeneration is supported by a wealth of literature showing the effect of mechanical stimuli on bone cell differentiation and matrix formation. Using mechanical stimuli, to our knowledge, has not been explored in vivo in bone tissue engineering applications. We thus propose to use an elastomeric platform, based on poly(glycerol sebacate (PGS), to mimic the natural biochemical environment of bone while enabling the transmission of mechanical forces. In this study we report the material's load-transducing ability as well as falling mechanically closer to bone marrow and osteoid tissue rather than to mature bone, allowed osteogenesis and bone maturation. Defying the notion of selecting bone regeneration scaffolds based on their relative mechanical comparability to mature bone, we consider our results in part novel for the new application of this elastomer and in another fostering for reassessment of the current selection criteria for bone scaffolds.
10.1016/j.actbio.2017.01.053
Accelerating bone regeneration using poly(lactic-co-glycolic acid)/hydroxyapatite scaffolds containing duck feet-derived collagen.
International journal of biological macromolecules
Collagen, with low antigenicity and excellent cell adhesion, is a biomaterial mainly used for regenerating bone, cartilage, and skin, owing to its biocompatibility and biodegradability. Results from a previous study confirmed that a scaffold mixed with duck feet-derived collagen (DC) and Poly(lactic-co-glycolic acid) (PLGA) reduced inflammatory reaction and increased bone regeneration. To develop an optimal bone substitute we included hydroxyapatite (HAp), a key osteoconductive material, in a DC and PLGA mixture. We fabricated 0, 10, 20, 40, 60, and 80 wt% DC/PLGA/HAp scaffolds and studied their potential for bone tissue engineering. Characteristic analysis of the scaffold and seeding of rabbit bone marrow mesenchymal stem cells (rBMSCs) on the scaffold were conducted to investigate cell proliferation, osteogenic differentiation, and bone formation. We confirmed that increasing DC concentration not only improved the compressive strength of the DC/PLGA/HAp scaffold but also cell proliferation and osteogenic differentiation. It was found through comparison with previous studies that including HAp in the scaffold also promotes osteogenic differentiation. Our study thus shows through in vivo results that the 80 wt% DC/PLGA/HAp scaffold promotes bone mineralization and collagen deposition while reducing the inflammatory response. Hence, 80 wt% DC/PLGA/HAp has excellent potential as a biomaterial for bone regeneration applications.
10.1016/j.ijbiomac.2022.12.296
The Metabolic Microenvironment Steers Bone Tissue Regeneration.
Loeffler Julia,Duda Georg N,Sass F Andrea,Dienelt Anke
Trends in endocrinology and metabolism: TEM
Over the past years, basic findings in cancer research have revealed metabolic symbiosis between different cell types to cope with high energy demands under limited nutrient availability. Although this also applies to regenerating tissues with disrupted physiological nutrient and oxygen supply, the impact of this metabolic cooperation and metabolic reprogramming on cellular development, fate, and function during tissue regeneration has widely been neglected so far. With this review, we aim to provide a schematic overview on metabolic links that have a high potential to drive tissue regeneration. As bone is, aside from liver, the only tissue that can regenerate without excessive scar tissue formation, we will use bone healing as an exemplarily model system.
10.1016/j.tem.2017.11.008
Porous nano-HA/collagen/PLLA scaffold containing chitosan microspheres for controlled delivery of synthetic peptide derived from BMP-2.
Niu Xufeng,Feng Qingling,Wang Mingbo,Guo Xiaodong,Zheng Qixin
Journal of controlled release : official journal of the Controlled Release Society
It is advantageous to incorporate controlled growth factor delivery into tissue engineering strategies. The purpose of the present study was to develop a novel tissue engineering scaffold with the capability of controlled releasing BMP-2-derived synthetic peptide. Porous nano-hydroxyapatite/collagen/poly(L-lactic acid)/chitosan microspheres (nHAC/PLLA/CMs) composite scaffolds containing different quantities of chitosan microspheres (CMs) were prepared by a thermally induced phase separation method. Dioxane was used as the solvent for PLLA. Introduction of less than 30% of CMs (on PLLA weight basis) did not remarkably affect the morphology and porosity of the nHAC/PLLA/CMs scaffolds. However, as the microspheres contents increased to 50%, the porosity of the composite decreased rapidly. The compressive modulus of the composite scaffolds increased from 15.4 to 25.5 MPa, while the compressive strength increased from 1.42 to 1.63 MPa as the microspheres contents increased from 0% to 50%. The hydrolytic degradation and synthetic peptide release kinetics in vitro were investigated by incubation in phosphate buffered saline solution (pH 7.4). The results indicated that the degradation rate of the scaffolds was increased with the enhancement of CMs dosage. The synthetic peptide was released in a temporally controlled manner, depending on the degradation of both incorporated chitosan microspheres and PLLA matrix. In vitro bioactivity assay revealed that the encapsulated synthetic peptide was biologically active as evidenced by stimulation of rabbit marrow mesenchymal stem cells (MSCs) alkaline phosphatase (ALP) activity. The successful microspheres-scaffold system offers a new delivery method of growth factors and a novel scaffold design for bone regeneration.
10.1016/j.jconrel.2008.11.020
Investigation of angiogenesis in bioactive 3-dimensional poly(d,l-lactide-co-glycolide)/nano-hydroxyapatite scaffolds by in vivo multiphoton microscopy in murine calvarial critical bone defect.
Li Jian,Xu Qiang,Teng Bin,Yu Chen,Li Jian,Song Liang,Lai Yu-Xiao,Zhang Jian,Zheng Wei,Ren Pei-Gen
Acta biomaterialia
UNLABELLED:Reconstruction of critical size bone defects remains a major clinical challenge because of poor bone regeneration, which is usually due to poor angiogenesis during repair. Satisfactory vascularization is a prerequisite for the survival of grafts and the integration of new tissue with existing tissue. In this work, we investigated angiogenesis in 3D scaffolds by in vivo multiphoton microscopy during bone formation in a murine calvarial critical bone defect model and evaluated bone regeneration 8weeks post-implantation. The continuous release of bioactive lentiviral vectors (LV-pdgfb) from the scaffolds could be detected for 5days in vitro. In vivo, the released LV-pdgfb transfected adjacent cells and expressed PDGF-BB, facilitating angiogenesis and enhancing bone regeneration. The expression of both pdgfb and the angiogenesis-related genes vWF and VEGFR2 was significantly increased in the pdgfb gene-carrying scaffold (PHp) group. In addition, microCT scanning and histomorphology results proved that there was more new bone ingrowth in the PHp group than in the PLGA/nHA (PH) and control groups. MicroCT parameters, including BMD, BV/TV, Tb.Sp, and Tb.N indicated that there was significantly more new bone formation in the PHp group than in the other groups. With regard to neovascularization, 8weeks post-implantation, blood vessel areas (BVAs) were 9428±944μm(2), 4090±680.3μm(2), and none in the PHp, PH, and control groups, respectively. At each time point, BVAs in the PHp scaffolds were significantly higher than in the PH scaffolds. To our knowledge, this is the first use of multiphoton microscopy in bone tissue-engineering to investigate angiogenesis in scaffolds in vivo. This method represents a valuable tool for investigating neovascularization in bone scaffolds to determine if a certain scaffold is beneficial to neovascularization. We also proved that delivery of the pdgfb gene alone can improve both angiogenesis and bone regeneration Acronyms. STATEMENT OF SIGNIFICANCE:Reconstruction of critical size bone defects remains a major clinical challenge because of poor bone regeneration, which is usually due to poor angiogenesis during repair. Satisfactory vascularization is a prerequisite for the survival of grafts and the integration of new tissue with existing tissue. In this work, we investigated angiogenesis in 3D scaffolds by in vivo multiphoton microscopy during bone formation in a murine calvarial critical bone defect model and evaluated bone regeneration 8weeks post-implantation. To verify that pdgfb-expressing vectors carried by the scaffolds can promote angiogenesis in 3D-printed scaffolds in vivo, we monitored angiogenesis within the implants by multiphoton microscopy. To our knowledge, this is the first study to dynamically investigate angiogenesis in bone tissue engineering scaffolds in vivo.
10.1016/j.actbio.2016.06.024
Theranostic Bioabsorbable Bone Fixation Plate with Drug-Layered Double Hydroxide Nanohybrids.
Kim Myung Hun,Hur Woojune,Choi Goeun,Min Hye Sook,Choi Tae Hyun,Choy Young Bin,Choy Jin-Ho
Advanced healthcare materials
A bioabsorbable polymeric bone plate enabled with both diagnostic and therapeutic functionalities (radiopacity and sustained drug release, respectively) is proposed. To this end, a drug-inorganic nanohybrid (RS-LDH) is examined as a theranostic agent by intercalating an anti-resorptive bone remodeling drug, risedronate (RS) into a layered double hydroxide (LDH) via an ion-exchange reaction. The RS-LDH is prepared as a sheet with a biodegradable polymer, poly(lactic-co-glycolic acid), and is then attached onto the clinically approved bioabsorbable bone plate to produce the theranostic plate. Because of the presence of the metals in the LDH, the theranostic plate results in discernible in vivo X-ray images for up to four weeks after implantation. Concurrently, bone regeneration is also significantly improved compared with the other control groups, likely because of this material's sustained drug-release property. The theranostic plate is also largely biocompatible, similar to the plate already approved for clinical use. It is concluded that the combination of a biodegradable bone plate with RS-LDH nanohybrids can constitute a promising system with theranostic ability in both X-ray diagnosis and expedited bone repair.
10.1002/adhm.201600761
Precisely controlled delivery of magnesium ions thru sponge-like monodisperse PLGA/nano-MgO-alginate core-shell microsphere device to enable in-situ bone regeneration.
Lin Zhengjie,Wu Jun,Qiao Wei,Zhao Ying,Wong Karen H M,Chu Paul K,Bian Liming,Wu Shuilin,Zheng Yufeng,Cheung Kenneth M C,Leung Frankie,Yeung Kelvin W K
Biomaterials
A range of magnesium ions (Mg) used has demonstrated osteogenic tendency in vitro. Hence, we propose to actualize this concept by designing a new system to precisely control the Mg delivery at a particular concentration in vivo in order to effectively stimulate in-situ bone regeneration. To achieve this objective, a monodisperse core-shell microsphere delivery system comprising of poly (lactic-co-glycolic acid) (PLGA) biopolymer, alginate hydrogel, and magnesium oxide nano-particles has been designed by using customized microfluidic capillary device. The PLGA-MgO sponge-like spherical core works as a reservoir of Mg while the alginate shell serves as physical barrier to control the outflow of Mg at ∼50 ppm accurately for 2 weeks via its adjustable surface micro-porous network. With the aid of controlled release of Mg, the new core-shell microsphere system can effectively enhance osteoblastic activity in vitro and stimulate in-situ bone regeneration in vivo in terms of total bone volume, bone mineral density (BMD), and trabecular thickness after operation. Interestingly, the Young's moduli of formed bone on the core-shell microsphere group have been restored to ∼96% of that of the surrounding matured bone. These findings indicate that the concept of precisely controlled release of Mg may potentially apply for in-situ bone regeneration clinically.
10.1016/j.biomaterials.2018.05.011
Polymeric electrospun scaffolds for bone morphogenetic protein 2 delivery in bone tissue engineering.
Aragón Javier,Salerno Simona,De Bartolo Loredana,Irusta Silvia,Mendoza Gracia
Journal of colloid and interface science
HYPOTHESIS:The development of novel scaffolds based on biocompatible polymers is of great interest in the field of bone repair for fabrication of biodegradable scaffolds that mimic the extracellular matrix and have osteoconductive and osteoinductive properties for enhanced bone regeneration. EXPERIMENTS:Polycaprolactone (PCL) and polycaprolactone/polyvinyl acetate (PCL/PVAc) core-shell fibers were synthesised and decorated with poly(lactic-co-glycolic acid) [PLGA] particles loaded with bone morphogenetic protein 2 (BMP2) by simultaneous electrospinning and electrospraying. Hydroxyapatite nanorods (HAn) were loaded into the core of fibers. The obtained scaffolds were characterised by scanning and transmission electron microscopy, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. The in vitro potential of these materials for bone regeneration was assessed in biodegradation assays, osteoblast viability assays, and analyses of expression of specific bone markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). FINDINGS:PLGA particles were homogeneously distributed in the entire fibre mat. The growth factor load was 1.2-1.7 μg/g of the scaffold whereas the HAn load was in the 8.8-12.6 wt% range. These scaffolds were able to support and enhance cell growth and proliferation facilitating the expression of osteogenic and osteoconductive markers (OCN and OPN). These observations underline the great importance of the presence of BMP2 in scaffolds for bone remodelling as well as the good potential of the newly developed scaffolds for clinical use in tissue engineering.
10.1016/j.jcis.2018.07.029
Ca-supplying black phosphorus-based scaffolds fabricated with microfluidic technology for osteogenesis.
Bioactive materials
Effective osteogenesis remains a challenge in the treatment of bone defects. The emergence of artificial bone scaffolds provides an attractive solution. In this work, a new biomineralization strategy is proposed to facilitate osteogenesis through sustaining supply of nutrients including phosphorus (P), calcium (Ca), and silicon (Si). We developed black phosphorus (BP)-based, three-dimensional nanocomposite fibrous scaffolds via microfluidic technology to provide a wealth of essential ions for bone defect treatment. The fibrous scaffolds were fabricated from 3D poly (l-lactic acid) (PLLA) nanofibers (3D NFs), BP nanosheets, and hydroxyapatite (HA)-porous SiO nanoparticles. The 3D BP@HA NFs possess three advantages: i) stably connected pores allow the easy entrance of bone marrow-derived mesenchymal stem cells (BMSCs) into the interior of the 3D fibrous scaffolds for bone repair and osteogenesis; ii) plentiful nutrients in the NFs strongly improve osteogenic differentiation in the bone repair area; iii) the photothermal effect of fibrous scaffolds promotes the release of elements necessary for bone formation, thus achieving accelerated osteogenesis. Both in vitro and results demonstrated that the 3D BP@HA NFs, with the assistance of NIR laser, exhibited good performance in promoting bone regeneration. Furthermore, microfluidic technology makes it possible to obtain high-quality 3D BP@HA NFs with low costs, rapid processing, high throughput and mass production, greatly improving the prospects for clinical application. This is also the first BP-based bone scaffold platform that can self-supply Ca, which may be the blessedness for older patients with bone defects or patients with damaged bones as a result of calcium loss.
10.1016/j.bioactmat.2021.04.014
Sonopiezoelectric Nanomedicine and Materdicine.
Small (Weinheim an der Bergstrasse, Germany)
Endogenous electric field is ubiquitous in a multitude of important living activities such as bone repair, cell signal transduction, and nerve regeneration, signifying that regulating the electric field in organisms is highly beneficial to maintain organism health. As an emerging and promising research direction, piezoelectric nanomedicine and materdicine precisely activated by ultrasound with synergetic advantages of deep tissue penetration, remote spatiotemporal selectivity, and mechanical-electrical energy interconversion, have been progressively utilized for disease treatment and tissue repair by participating in the modulation of endogenous electric field. This specific nanomedicine utilizing piezoelectric effect activated by ultrasound is typically regarded as "sonopiezoelectric nanomedicine". This comprehensive review summarizes and discusses the substantially employed sonopiezoelectric nanomaterials and nanotherapies to provide an insight into the internal mechanism of the corresponding biological behavior/effect of sonopiezoelectric biomaterials in versatile disease treatments. This review primarily focuses on the sonopiezoelectric biomaterials for biosensing, drug delivery, tumor therapy, tissue regeneration, antimicrobia, and further illuminates the underlying sonopiezoelectric mechanism. In addition, the challenges and developments/prospects of sonopiezoelectric nanomedicine are analyzed for promoting the further clinical translation. It is earnestly expected that this kind of nanomedicine/biomaterials-enabled sonopiezoelectric technology will provoke the comprehensive investigation and promote the clinical development of the next-generation multifunctional materdicine.
10.1002/smll.202301693
Bioinspired Mild Photothermal Effect-Reinforced Multifunctional Fiber Scaffolds Promote Bone Regeneration.
ACS nano
Bone fractures are often companied with poor bone healing and high rates of infection. Early recruitment of mesenchymal stem cells (MSCs) is critical for initiating efficient bone repair, and mild thermal stimulation can accelerate the recovery of chronic diseases. Here, a bioinspired, staged photothermal effect-reinforced multifunctional scaffold was fabricated for bone repair. Uniaxially aligned electrospun polycaprolactone nanofibers were doped with black phosphorus nanosheets (BP NSs) to endow the scaffold with excellent near-infrared (NIR) responsive capability. Apt19S was then decorated on the surface of the scaffold to selectively recruit MSCs toward the injured site. Afterward, microparticles of phase change materials loaded with antibacterial drugs were also deposited on the surface of the scaffold, which could undergo a solid-to-liquid phase transition above 39 °C, triggering the release of payload to eliminate bacteria and prevent infection. Under NIR irradiation, photothermal-mediated up-regulation of heat shock proteins and accelerated biodegradation of BP NSs could promote the osteogenic differentiation of MSCs and biomineralization. Overall, this strategy shows the ability of bacteria elimination, MSCs recruitment, and bone regeneration promotion with the assistance of photothermal effect and , which emphasizes the design of a bioinspired scaffold and its potential for a mild photothermal effect in bone tissue engineering.
10.1021/acsnano.2c11486
Nanomedicine for safe healing of bone trauma: Opportunities and challenges.
Biomaterials
Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches.
10.1016/j.biomaterials.2017.09.005
Targeted nanomedicines for the treatment of bone disease and regeneration.
Ordikhani Farideh,Zandi Nooshin,Mazaheri Mozhdeh,Luther Gaurav A,Ghovvati Mahsa,Akbarzadeh Abolfazl,Annabi Nasim
Medicinal research reviews
Targeted delivery by either passive or active targeting of therapeutics to the bone is an attractive treatment for various bone related diseases such as osteoporosis, osteosarcoma, multiple myeloma, and metastatic bone tumors. Engineering novel drug delivery carriers can increase therapeutic efficacy and minimize the risk of side effects. Developmnet of nanocarrier delivery systems is an interesting field of ongoing studies with opportunities to provide more effective therapies. In addition, preclinical nanomedicine research can open new opportunities for preclinical bone-targeted drug delivery; nevertheless, further research is needed to progress these therapies towards clinical applications. In the present review, the latest advancements in targeting moieties and nanocarrier drug delivery systems for the treatment of bone diseases are summarized. We also review the regeneration capability and effective delivery of nanomedicines for orthopedic applications.
10.1002/med.21759
The advances in nanomedicine for bone and cartilage repair.
Journal of nanobiotechnology
With the gradual demographic shift toward an aging and obese society, an increasing number of patients are suffering from bone and cartilage injuries. However, conventional therapies are hindered by the defects of materials, failing to adequately stimulate the necessary cellular response to promote sufficient cartilage regeneration, bone remodeling and osseointegration. In recent years, the rapid development of nanomedicine has initiated a revolution in orthopedics, especially in tissue engineering and regenerative medicine, due to their capacity to effectively stimulate cellular responses on a nanoscale with enhanced drug loading efficiency, targeted capability, increased mechanical properties and improved uptake rate, resulting in an improved therapeutic effect. Therefore, a comprehensive review of advancements in nanomedicine for bone and cartilage diseases is timely and beneficial. This review firstly summarized the wide range of existing nanotechnology applications in the medical field. The progressive development of nano delivery systems in nanomedicine, including nanoparticles and biomimetic techniques, which are lacking in the current literature, is further described. More importantly, we also highlighted the research advancements of nanomedicine in bone and cartilage repair using the latest preclinical and clinical examples, and further discussed the research directions of nano-therapies in future clinical practice.
10.1186/s12951-022-01342-8
Bioceramics: from bone regeneration to cancer nanomedicine.
Vallet-Regí María,Ruiz-Hernández Eduardo
Advanced materials (Deerfield Beach, Fla.)
Research on biomaterials has been growing in the last few years due to the clinical needs in organs and tissues replacement and regeneration. In addition, cancer nanomedicine has recently appeared as an effective means to combine nanotechnology developments towards a clinical application. Ceramic materials are suitable candidates to be used in the manufacturing of bone-like scaffolds. Bioceramic materials may also be designed to deliver biologically active substances aimed at repairing, maintaining, restoring or improving the function of organs and tissues in the organism. Several materials such as calcium phosphates, glasses and glass ceramics able to load and subsequently release in a controlled fashion drugs, hormones, growth factors, peptides or nucleic acids have been developed. In particular, to prevent post surgical infections bioceramics may be surface modified and loaded with certain antibiotics, thus preventing the formation of bacterial biofilms. Remarkably, mesoporous bioactive glasses have shown excellent characteristics as drug carrying bone regeneration materials. These bioceramics are not only osteoconductive and osteoproductive, but also osteoinductive, and have therefore been proposed as ideal components for the fabrication of scaffolds for bone tissue engineering. A recent promising development of bioceramic materials is related to the design of magnetic mediators against tumors. Magnetic composites are suitable thermoseeds for cancer treatment by hyperthermia. Moreover, magnetic nanomaterials offer a wide range of possibilities for diagnosis and therapy. These nanoparticles may be conjugated with therapeutic agents and heat the surrounding tissue under the action of alternating magnetic fields, enabling hyperthermia of cancer as an effective adjunct to chemotherapy regimens.
10.1002/adma.201101586
Biomaterials and nanomedicine for bone regeneration: Progress and future prospects.
Exploration (Beijing, China)
Bone defects pose a heavy burden on patients, orthopedic surgeons, and public health resources. Various pathological conditions cause bone defects including trauma, tumors, inflammation, osteoporosis, and so forth. Auto- and allograft transplantation have been developed as the most commonly used clinic treatment methods, among which autologous bone grafts are the golden standard. Yet the repair of bone defects, especially large-volume defects in the geriatric population or those complicated with systemic disease, is still a challenge for regenerative medicine from the clinical perspective. The fast development of biomaterials and nanomedicine favors the emergence and promotion of efficient bone regeneration therapies. In this review, we briefly summarize the progress of novel biomaterial and nanomedical approaches to bone regeneration and then discuss the current challenges that still hinder their clinical applications in treating bone defects.
10.1002/EXP.20210011
An injectable and thermosensitive hydrogel with nano-aided NIR-II phototherapeutic and chemical effects for periodontal antibacteria and bone regeneration.
Journal of nanobiotechnology
Periodontitis is a common public health problem worldwide and an inflammatory disease with irregular defect of alveolar bone caused by periodontal pathogens. Both antibacterial therapy and bone regeneration are of great importance in the treatment of periodontitis. In this study, injectable and thermosensitive hydrogels with 3D networks were used as carriers for controlled release of osteo-inductive agent (BMP-2) and Near Infrared Region-II (NIR-II) phototherapy agents (T8IC nano-particles). T8IC nano-particles were prepared by reprecipitation and acted as photosensitizer under 808 nm laser irradiation. Besides, we promoted photodynamic therapy (PDT) through adding HO to facilitate the antibacterial effect instead of increasing the temperature of photothermal therapy (PTT). Hydrogel + T8IC + Laser + BMP-2 + HO incorporated with mild PTT (45 °C), enhanced PDT and sustained release of BMP-2. It was present with excellent bactericidal effect, osteogenic induction and biosafety both in vitro and in vivo. Besides, immunohistochemistry staining and micro-CT analyses had confirmed that PTT and PDT could promote bone regeneration through alleviating inflammation state. Altogether, this novel approach with synergistic antibacterial effect, anti-inflammation and bone regeneration has a great potential for the treatment of periodontitis in the future.
10.1186/s12951-023-02124-6