Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration
Abstract
:1. Introduction
2. Protection from Physical and Enzymatic Degradation
2.1. Usage of Carriers to Protect Growth Factors
2.2. Engineering Proteins to Increase Stability of GFs
3. Targeted Delivery of Growth Factors
3.1. Active Delivery with Bone/Cartilage Targeting Motifs
3.2. Enhancing Growth Factor Retention in Delivery Scaffolds
4. Controlling GF Release Kinetics
4.1. Short-Term Release
4.2. Long-Term Release
4.3. Synergistic Delivery of Multiple GFs
4.4. Sequential Delivery
4.5. Spatial Control
5. Promoting the Long-term Stability of Regenerated Tissues
6. Osteoimmunomodulatory (OIM) Effects
7. Conclusions and Remarks for Future Research
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Bone/Cartilage Targeting Motif | Structure/Sequence | Target Tissue | Conjugated Protein/Nanoparticles | Result | Ref. |
---|---|---|---|---|---|
Bisphosphonates(BPs) | R = single atoms, alkyl chains, amino group etc. | Bone | Osteoprotegerin (OPG) | Four folds increase in targeting bone (tibia) in comparison to OPG only group. | [30] |
Superoxide dismutase (SOD) | BP conjugation achieved 36% of delivery rate while SOD alone showed no accumulation to bone. | [31] | |||
Salmon calcitonin | 4 folds increase in targeting bone mineral component compared to GF only control. | [32] | |||
Tetracycline | Simvastatin | Preferential accumulation of simvastatin in bone tissue was observed in comparison to simvastatin only control. | [34] | ||
Peptide sequences | CARSKNKDC | Tendon | N/A | CAR sequence was accumulated at tendon and skin in vitro and in vivo. | [36] |
DDDDDDDC (Poly-Asp) | Bone | P28 (BMP2 related peptide) | Conjugation of poly-asp with P28 to achieve targeted delivery. | [38,39] | |
SDSSD | Osteoblast | anti-miR-214 in polyurethane nanomicelles | SDSSD peptide selectively bound to osteoblast via periostin in vitro, improving the delivery efficiency in vivo with mice osteoporosis model. | [40] | |
EPLQLKM | Cartilage | Kartogenin | MSC-targeting sequence (EPLQLKM) improved the efficiency of KGN delivery to MSCs in vitro and enhanced cartilage regeneration in vivo. | [41] | |
DWRVIIPPRPSA | mi-RNA 140 | Chondrocyte targeting sequence was encoded after exosome enriched protein, allowing targeted delivery of drug in exosome. | [43] | ||
Aptamer | Bone | siRNA | Osteoblast-specific aptamer-decorated liposome was used to deliver siRNA to bone and promoted osteoblast function. | [47] | |
Antibody | scFv | Cartilage | IGF1 | Conjugation of IGF1 with scFV targeting matrilin-3 showed enhanced IGF1 accumulation at cartilage and reduced off-target delivery at other organ. | [56] |
Synovium | scFv-anti-TNFa (Adalimumab) and scFv-A7 | Bispecific antibody; one targeting to TNFa to suppress inflammation and other end targeting to synovium (scFV-A7). Results showed successful accumulation at xenografted human synovium in mice. | [57] |
Protein | Scaffold | Method | Result | Ref. |
---|---|---|---|---|
BMP2 | Collagen | Affinity | Heparin was immobilized to collagen scaffold to achieve the spatial localization of BMP2, successfully reducing the heterotopic bone formation. | [60] |
PDGF-BB BMP2 | PCL | GFs were immobilized on heparin coated PCL scaffold. Continuous release of initial loading amount after 5 weeks without an initial burst were observed, leading to better tendon regeneration. | [62] | |
P24 | nHA/RHLC/PLA | Polydopamin was coated on nHA/RHLC/PLA to have an affinity to P24, resulting slower release/high retention. | [63] | |
BMP2 BMP7 | Fibrin | Covalent | Covalent conjugation allowed slower release kinetics in vitro. Enhanced bone regeneration was observed in critical size calvarial defects model with rat. | [65] |
TGFβ3 | PLGA-GCH | Prolonged release of TGFβ and improved cartilage regeneration were observed. | [66] | |
BMP2 | Collagen | Engineered bridge | Dual affinity bridge protein connected collagen scaffold and BMP2. Lower BMP2 dosage was required to induce bone formation in vivo. | [68] |
Collagen/alginate/Titanium | Antibody | BMP2 mAbs was immobilized to scaffold to capture endogenous BMP-2 for bone regeneration, improving bone formation in rat calvarial defects model. | [69] | |
BMP2 FGF2 | Gelatin | Biotin-avidin | Biotinylated BMP2 and FGF2 were bound to avidin functionalized nanofiber, showing controlled release of BMP2 and FGF2. | [70] |
Materials | Modification | Protein | Target | Release Duration | Result | Ref. | |
---|---|---|---|---|---|---|---|
Natural | Alginate sulfate | Sulfation | bFGF | Vascular | 5 days | Slower release with sulfate-conjugated alginate. Sulfated alginate released 50% of bFGF by day 5 while control alginate released 50% of bFGF at day 0. | [75] |
TGFb | Cartilage | 7 days | The sulfate group exhibited an affinity for TGFb, resulting in a slower release rate compared to non-sulfated alginate. | [76] | |||
Gelatin-PCL | N/A | BMP2 | Bone | 10–45 days | Gelatin/heparin gel enhanced cells viability and PCL enhanced mechanical property. Release kinetics was controllable by combining gelatin and PCL. | [77] | |
Liposome | 100 hours | Achieved steady release of rh-BMP2 for 100 hours in vitro. | [78] | ||||
Chitosan | Thiolation | BMP2 | Bone | 14 days | The thiolate modification contributed to the upregulation of ALP activity and better bone regeneration by prolonging the release of BMP2. | [79] | |
Synthetic | PEG-based hydrogel | PLGA microparticle | BMP2 | Bone | 3 days | BMP-2 was encapsulated within PLGA microparticles, which were further enclosed within a PEG-based hydrogel. Initially, 75% of the BMP-2 was released within 3 days. | [80] |
N/A | bFGF | Cartilage | 60 days (BSA) 35 days (FGF) | Hydrolytically degradable structures increased the hydrogel swelling ratio and mesh size, enabling sustained protein release over 2 months. | [81] | ||
P34HB nanoparticles | Soybean coating | BMP7 | Bone | 20 days | Soybean coating on nanoparticle significantly slowed down BMP7 release kinetics. | [83] | |
Mesoporous silica in Hydrogel | Dopamine coating | TGFb3 | Cartilage | 75 days | TGFb3 was loaded in mesoporous silica coated with DOPA. Thicker DOPA coating achieved slower release and achieved 75 days release duration in vitro. | [84] | |
PLGA particle in poly(LLA-co-CL) | N/A | BMP2 | Bone | 70 days | BMP2 was incorporated in PLGA microsphere, which were further encapsulated in scaffold. Result showed better bone formation in rat calvarial model. | [85] | |
Mesoporous silica in PLGA | BMP2 | Bone | 40 days | BMP2 was incorporated in Mesoporous silica, then mixed with PLGA to create microsphere. In vitro functional assay showed improved bone formation. | [86] | ||
MBG/SIS scaffold | Heparin | P28 | Bone | 40 days | BMP2 was incorporated in MBG, which were further encapsulated in SIS. Enhanced bone regeneration was observed in rat calvarial defect model. | [87] | |
Hybrid | hyaluronate/type I collagen/fibrin composite containing PVA nanofibers enriched with liposomes | N/A | bFGF Insulin | Cartilage | 19 days | Achieved steady release of both bFGF and insulin for 19 days in vitro. Nanofiber provided mechanical stiffness and elasticity closer to native cartilage. In vivo mini-pig experiment demonstrated cartilage regeneration. | [88] |
System | Protein | Target | Mechanism | Release Kinetics/Spatial Release Strategy | Result | Ref. |
---|---|---|---|---|---|---|
Synergistic | BMP7 & BMP2 | Bone | BMP7 and BMP2 were loaded in PELA microparticle. | BMP7 and BMP2 showed steady release for 42 days in vitro. | In vivo rat femoral defect model demonstrated improved bone regeneration. | [89] |
BMP7 & TGFb3 | Cartilage | BMP7 and TGFb were loaded in PLGA microsphere. | BMP7 and TGFb showed steady release for 30 days in vitro. | Synergistic effect of chondrogenic promotion in vitro. | [90] | |
BMP2 & VEGFR | Cartilage | BMP2 and VEGFR were loaded in PEG based hydrogel. | BMP2 promoted osteogenic differentiation of SSCs, which was further directed to chondrocyte with VEGFR. | Implantation of hydrogel containing BMP2 and VEGFR at femoral defect promoted cartilage formation. | [91] | |
BMP2 & Melatonin | Bone | BMP2 and Melatonin were loaded in PLGA microparticle, which is further encapsulated in Chitosan-Hap scaffold. | BMP2 and melatonin showed steady release for 20 days in vitro. | Improved osteogenic ability was confirmed by alizarin red and ALP-von Kossa staining using MC3T3-E1 cells. | [94] | |
Sequential delivery | BMP2 & Dex | Bone | BMP2 is encapsulated in chitosan particle, which is further incorporated in PCE nanofiber with DEX. | Dex exhibited a burst release during the first 5 days, whereas BMP2 displayed a consistent release over 35 days. | Dual delivery demonstrated a better bone regeneration in rat calvarial bone defect. | [97] |
BMP2 & ALN | Bone | ALN is encapsulated in PLGA microsphere, which is further incorporated in collagen hydroxyapatite. | The release profile of BMP2 exhibited a burst kinetics for the first 5 days, whereas ALN demonstrated a delayed release between 2 to 6 weeks. | Dual delivery demonstrated a better bone regeneration in rat calvarial bone defect. | [98] | |
BMP2 & IGF | Bone | BMP2 was encapsulated in the 1st gelatin layer and BMP2 and IGF were loaded in the 2nd gelatin layer. | BMP2 in 1st layer was released in 2 days and 2nd layer in 6 days. | Increased AP activity and matrix calcium content compared to control. | [100] | |
SDF1 & BMP2 | Bone | BMP2 is encapsulated in silk fibroin particle, which is further incorporated in Hap scaffold with SDF1. | SDF1 demonstrated a burst release for first 5 days while BMP2 showed steady release for 35 days. | Dual delivery showed a better bone regeneration in rat calvarial bone defect. | [101] | |
TGFb & BMP2 | Cartilage | TGFb is encapsulated in gelatin microparticle and BMP2 in mineral-coated hydroxyapatite microparticles. | TGFb displayed an initial burst release for 10 days and sustained BMP2 release for 60 days. | Dual delivery resulted in an enhanced GAG and Col2 expression, as demonstrated by immunostaining. | [102] | |
IGF1& TGFb1 | Cartilage | IGF1 is incorporated in gelatin microparticle, which is encapsulated in OPF with TGFb. | An initial burst release of TGFb was observed, followed by a slower release of IGF1. | The release kinetics were able to be adjusted by modifying the crosslinking amount. | [103] | |
IL-8 & BMP2 | Bone | BMP2 is incorporated in mesoporous bioactive glass (MBG) which is coated by PEG with IL-8. | Initial burst release of IL-8 for 1 day and steady release of BMP2 for 7 days. | The recruitment of stem cells by IL-8 and the promotion of osteogenesis by BMP2 resulted in enhanced bone regeneration. | [104] | |
Spatial control | bFGF & BMP4 | Bone& Cartilage | Use high affinity between sulfate and proteins to control spatial distribution. | Two layered alginate-sulfate: One layer with bFGF, another one with BMP. | bFGF induced chondrogenic differentiation. BMP4 induced endochondral ossification of endogenous cells. | [105] |
BMP2 & TGFb | Bone& Cartilage | hyaluronic acid hydrogel was filled in porous PLGA scaffold. | BMP2 adsorbed to PLGA scaffold and TGFb incorporated in the hydrogel. Gradient was created by these 2 layers. | Cartilaginous regions were marked by increased GAG production, and osteogenesis was seen in the graft. | [106] |
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Takematsu, E.; Murphy, M.; Hou, S.; Steininger, H.; Alam, A.; Ambrosi, T.H.; Chan, C.K.F. Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration. Gels 2023, 9, 377. https://doi.org/10.3390/gels9050377
Takematsu E, Murphy M, Hou S, Steininger H, Alam A, Ambrosi TH, Chan CKF. Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration. Gels. 2023; 9(5):377. https://doi.org/10.3390/gels9050377
Chicago/Turabian StyleTakematsu, Eri, Matthew Murphy, Sophia Hou, Holly Steininger, Alina Alam, Thomas H. Ambrosi, and Charles K. F. Chan. 2023. "Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration" Gels 9, no. 5: 377. https://doi.org/10.3390/gels9050377