Recent Advances in the Hydrogel-Based Biomolecule Delivery System for Cartilage Tissue Engineering

Guan, Jingyan; Feng, Jingwei; Lu, Feng

doi:https://doi.org/10.1155/2022/1899400

Advances in Materials Science and Engineering

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Abstract Introduction Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 1899400 | https://doi.org/10.1155/2022/1899400

Recent Advances in the Hydrogel-Based Biomolecule Delivery System for Cartilage Tissue Engineering

Jingyan Guan,¹Jingwei Feng,¹and Feng Lu¹

Academic Editor: Ramadhansyah Putra Jaya

Received25 Jul 2022

Revised22 Sept 2022

Accepted26 Sept 2022

Published22 Oct 2022

Abstract

Many investigations have been conducted to explore new therapeutic approaches for cartilage tissue regeneration owing to the limited repair ability of cartilage. Delivery of therapeutic biomolecules is a promising strategy for enhancing tissue regeneration. However, the direct delivery of therapeutic biomolecules in vivo generally leads to a rapid loss of product or the possibility of spreading to nontarget sites, which may weaken their therapeutic effectiveness and impair the translation of these strategies into clinical practice. Recently, new tissue engineering strategies using controlled delivery systems have been considered to overcome these weaknesses by regulating the spatiotemporal distribution of the therapeutic biomolecules. Hydrogels are promising carriers for the development of biomolecule delivery systems because they are highly tunable and can be fabricated to encapsulate bioactive biomolecules and control their release. Moreover, their favorable biocompatibility and ability to integrate into host tissue may facilitate their use in tissue regeneration in a wide variety of situations. This review summarizes recent strategies for the design of hydrogels as biomolecule delivery systems for cartilage regeneration.

1. Introduction

Cartilage is the load-bearing tissue of the body. Trauma and aging often damage or disrupt the structure and function of cartilage, and even minor defects can result in mechanical joint instability or progressive damage. The repair and regeneration of articular cartilage tissue remains an open challenge owing to its avascular and alymphatic nature [1–4]. Current therapeutic approaches for repairing damaged cartilage include autologous chondrocyte implantation, arthroscopic microfracture, and open procedures such as osteotomy and arthroplasty. However, the repaired cartilage does not have the structure of native cartilage, and these procedures generally result in the formation of fibrocartilage and continued pain and discomfort [5]. To address this, cartilage tissue engineering (CTE) approaches that aim to develop constructs that regenerate healthy and fully functional cartilage are being actively investigated [6]. Ideally, these tissue-engineered constructs should generate neocartilage that is biochemically and biomechanically identical to native cartilage.

The ideal CTE scaffold should possess the following characteristics: high biodegradability, adhesion to host tissue, and good nutrient permeability. Polymeric hydrogels are promising as scaffolding because of their highly hydrated nature, tunable mechanical properties, good biocompatibility, controllable degradation rate [7], and ability to encapsulate cells and biomolecules [8]. Additionally, the spatiotemporal organization of therapeutic biological signals is important for tissue and organ regeneration; to address this, numerous studies have developed biomaterial-based delivery systems to regulate cell behavior by topically and continuously delivering therapeutic biomolecules to a target location [9, 10]. Polymeric hydrogels are also promising as drug delivery platforms for CTE because they can be designed to provide a physiological microenvironment for the encapsulation of therapeutic biomolecules. In addition, stimuli-responsive hydrogels, which contain stimuli-responsive units that exhibit a phase transition ability in response to stimuli [11], have been explored for controlled drug release [12–14]. Stimuli-responsive hydrogels show stimuli-induced structural and volume transitions, thus providing several multidimensional applications in regenerative medicine [15]. Therefore, this review addresses recent advances in hydrogel scaffolds as therapeutic biomolecule delivery platforms for cartilage regeneration.

2. Design Specifications of Hydrogel

The use of hydrogels as drug delivery platforms for CTE should satisfy several specific requirements: 1. the degradation of hydrogels should occur in a controlled manner without cytotoxic by-products; 2. the inner pores of hydrogels should be of an appropriate size and density to ensure a high diffusion and binding of labile biomolecules throughout the scaffold; 3. the release of biomolecules should be controllable and able to be delivered to targeted cells; 4. the hydrogels should support the viability, proliferation, and chondrocytic phenotype of the encapsulated cells; 5. the hydrogels should be able to integrate with the surrounding host cartilage tissue; and 6. the hydrogels should be able to be delivered in a minimally invasive manner (e.g., injection).

Hydrogels can be synthesized using natural, synthetic, or hybrid polymer backbones. Natural hydrogels have favorable biodegradability and biocompatibility, with properties similar to those of natural extracellular matrix (ECM). The most widely used natural hydrogels for CTE include alginate [16–19], hyaluronic acid (HA) [20–23], and fibrin [24–26]. The disadvantages of natural hydrogels include inconsistent hydration and poor mechanical properties. Additionally, the widespread application of these natural polymers is limited by their low production and complex purification from organisms. Furthermore, their poor flexibility often restricts the tailoring extent of hydrogel properties.

The properties of synthetic hydrogels are more tailorable [27]. The most widely used synthetic hydrogels for CTE include poly(lactide-co-glycolide) (PLGA) [28, 29], polyethylene glycol (PEG) [30], and poly((meth)acrylic acid) p((M)AA) [31]. Characteristic advantages of these synthetic polymers are their broad modification possibilities such as stiffness, porosity, mesh size, and degradation profiles. These properties are important for drug delivery, as the binding and controlled release of biomolecules depend on the structural properties of the chosen hydrogel [32–34]. Moreover, synthetic hydrogels can be designed to be responsive to certain stimuli (e.g., ionic concentration, temperature, and pH), which is beneficial for CTE. However, synthetic hydrogels lack the inherent biocompatibility and cell bioactivity properties compared with natural polymers.

Hybrid hydrogels are complexes composed of two or more natural or synthetic polymers, which often compensate for the shortcomings of both [35]. In general, the components of a hybrid hydrogel are interconnected through physical or chemical means such as electrostatic/ionic interactions [36], crosslinking [37], or irradiation [38, 39]. The combination of natural and synthetic polymers can create hydrogel scaffolds with good physiochemical properties and biocompatibility, making them more suitable for use in drug delivery [40]. For example, some previous studies have reported that synthetic polymers have problems with initial burst release of drugs [41], but the incorporation of natural polymers improves control over the release of biomolecules [42].

Pore size and interconnectivity are critical parameters that determine scaffold performance in CTE. Cell adhesion, viability, migration, and morphology are strongly correlated with the scaffold pore size [43, 44]. Porosity and pore structure also have a strong influence on nutrient and waste transference [43, 45]. Hydrogels are attractive candidates for designing cell-loading scaffolds because of their highly tunable properties. Although extensive research studies have been carried out on the influence of hydrogel scaffold porosity and pore size on their effectiveness as CTE tools [46–51], their optimal porosity and pore size for chondrocyte adhesion, proliferation, and differentiation have not been standardized because of the wide variety of hydrogel materials, synthesis techniques, seed cell sources, and application conditions. It has been reported that, when compared to materials with larger pores, hydrogel materials with smaller pores are preferable for chondrocyte proliferation and expression of cartilaginous markers [49]. For instance, Zhang et al. prepared collagen scaffolds with different ranges of pore sizes (150–250, 250–355, 355–425, and 425–500 μm) to investigate the effect of pore size on the biological behavior of seeded chondrocytes. Their results indicated that the scaffold pore size did not significantly affect the proliferation of chondrocytes; however, cartilage regeneration was obviously affected, with a diameter of 150–250 μm exhibiting the best improvement in the expression and production of type II collagen (Col II) and aggrecan [47]. Similarly, Nava et al. found that a poly(L-lactide-co-trimethylene carbonate) scaffold with 175 μm pore size and 87% porosity was suitable for the proliferation of chondrocytes, whereas scaffolds with a smaller pore size (75 μm) and porosity (75%) were more beneficial to cell metabolic activity and the synthesis of cartilaginous matrix proteins [48]. However, some studies have shown that scaffolds with larger pore sizes improve chondrogenesis. Lien et al. fabricated a series of gelatin scaffolds with pore sizes ranging from 50 to 500 μm by varying the crosslinking temperature (10–25°C). In vitro experiments showed that chondrocytes in the scaffolds with larger pores (250–500 µm) exhibited an increased proliferation and ECM secretion, whereas the cells in scaffolds with smaller pores often dedifferentiated [52]. Therefore, the pore size of cell-loaded hydrogels should be adjusted according to the conditions they will be operating under for better cartilage tissue regeneration results.

3. General Synthesis Schemes of Hydrogels

Hydrogels are mainly fabricated by the formation of crosslinked polymeric networks via physical or chemical processes. Physical crosslinking is normally achieved via methods such as ionic/electrostatic interactions [53, 54], hydrophobic interactions [55], crystallization [56], polymer chain complexation [57], and hydrogen bonding [58]. The main advantage of physical crosslinking is biomedical safety owing to the absence of chemical agents during gelation [59]. Because physically crosslinked hydrogels do not form covalent bonds, their synthesis is reversible, but they are generally unstable under physiological conditions. Chemical crosslinking strategies include enzyme-induced crosslinking [60, 61], photopolymerization [62], and “click” chemistry reactions [63]. Unlike physically crosslinked hydrogels, chemically crosslinked hydrogels form covalent bonds; the synthesis of chemically crosslinked hydrogels is therefore irreversible. They are also more stable under physiological conditions and possess better mechanical strength. However, the use of organic catalysts and solvents in chemical crosslinking may introduce environmental and biocompatibility problems [64]. Therefore, to minimize the limitations of physical or chemical crosslinking while combining their advantages, an increasing effort has focused on the fabrication of hydrogels using hybrid crosslinking techniques [65]. For example, Zhong et al. developed a single-network poly(acrylic acid) (PAA) hydrogel using a combination of ionic and covalent crosslinking [66], resulting in superior mechanical properties and water absorbency.

4. Signaling Biomolecules in Cartilage Regeneration

Cartilage regeneration is a developmental process controlled and coordinated by many signaling factors. These signaling molecules initiate or suppress cellular signaling pathways, which subsequently determine cell fates [67–69]. Therefore, the selection of appropriate factors is critical for the design of a controlled delivery system. Currently, the most investigated signaling factors in CTE are transforming growth factor-beta (TGF-β), bone morphogenetic protein (BMP), insulin-like growth factor-1 (IGF-1), and fibroblast growth factors (FGFs) [70, 71] (Figure 1).

The TGF-β superfamily, which has over 30 members, is a group of versatile cytokines involved in the regulation of cartilage homeostasis and regeneration [72, 73]. Among all TGF-β family members, TGF-β3 isoforms are considered to have the highest chondrogenic potential [74]. Various TGF-β isoforms are activated during cartilage regeneration; these not only promote proteoglycan and Col II synthesis but also prevent the degradation of cartilage ECM [75, 76]. As a member of the TGF-β family, BMP is responsible for the regulation of cartilage growth and resorption. BMP signaling is necessary for the initiation of prechondrogenic condensation and chondrocyte maturation [77]. In particular, BMP-2 affects cellular proliferation and induces the rapid maturation of chondrocytes, BMP-4 participates in the synthesis of aggrecan and Col II, and BMP-7 protects chondrocytes by improving their anabolism and ability to repair damaged cartilage [78]. Mechanism analysis has demonstrated that TGF-β signals bind to the receptor TGF-β-RII, which recruits and phosphorylates TGF-β-RI, leading to the phosphorylation and activation of intracellular SMA- and MAD-related (SMAD) superfamily signals. Activated SMAD proteins form a heterocomplex with SMAD4 and other co-activators, then translocate to the nucleus to regulate chondrogenic gene expression [70].

IGF-1 is a hormone similar in molecular structure to that of insulin and is recognized as a key factor in the regulation of cell proliferation and inhibition of cell death. In cartilage tissue, IGF-1 signaling occurs in the synovial fluid of the joint and regulates the expression of various chondrogenic markers [79, 80]. IGF-1 may also modulate mesenchymal stem cell (MSC) chondrogenesis by inducing cellular proliferation and the expression of chondrocyte markers via the extracellular signal-related kinase 1/2 mitogen-activated protein kinase (Erk1/2 MAPK) pathway [70, 81, 82].

FGFs are a family of cell signaling proteins that participate in various physiological processes and play a crucial role in tissue development. Any dysfunction in FGFs may result in developmental defects [83]. FGFs are generally found in the ECM of cartilage. They are activated upon tissue loading and reduce aggrecanase activity [84]. It has been reported that the knockout of FGF-2 accelerates osteoarthritis, whereas the subcutaneous administration of FGF-2 suppresses osteoarthritis in a mouse model [85]. FGF-2 treatment of bone marrow-derived MSCs enhanced chondrogenic differentiation in subsequent 3-dimensional (3D) cultures [86]. Intra-articular administration of FGF-18 can alleviate cartilage degeneration and increase cartilage thickness in a rat osteoarthritis (OA) model, but it also increases synovial thickness and chondrophyte formation [87]. It has also been demonstrated that FGFs markedly enhance chondrogenic marker SOX9 expression in both chondrocytes and prechondrocytic cells via the activation of the mitogen-activated protein kinase (MAPK) pathway [88]. However, the literature regarding the role of FGFs in cartilage regeneration is limited, and the precise mechanisms remain to be defined.

5. Strategies for Controlling Delivery of Therapeutic Biomolecules from Hydrogels

Strategies to precisely deliver biomolecules locally and continuously are gaining popularity in the field of CTE [89, 90]. In the past few decades, researchers have applied a variety of techniques and scaffold materials to develop controlled therapeutic biomolecule delivery systems. However, tissue regeneration is a complex biological process that requires a precise regulation of the spatial and temporal gradients of various therapeutic biomolecules [91]. Because of this, their delivery should be spatiotemporally regulated for maximum efficacy [92]. Therefore, it is necessary to select appropriate polymer combinations and drug-loading methods and to adjust parameters such as the proportion, particle size, shape, and surface morphology of hydrogels for a specific therapeutic site [40]. The following sections discuss the recent progress in hydrogel-based therapeutic biomolecule delivery strategies for cartilage regeneration and highlight the recent developments that allow precise spatiotemporal control over biomolecule delivery in hydrogels.

6. Growth Factor Delivery Platform using Hydrogel Scaffold for Cartilage Regeneration

6.1. Direct Physical Entrapment and Chemical Conjugation of Growth Factors

The spatiotemporal organization of the growth factors in the polymeric matrix is critical for tissue regeneration, and bioactivity is affected by several parameters, including the pH, temperature, and porosity of the matrix [40]. With the deepening understanding of the signaling factors that regulate cell fate, the construction of hydrogel scaffolds used for cartilage regeneration has become increasingly sophisticated. Among all the spatiotemporal control strategies, most technical methods include physical entrapment and chemical conjugation. These approaches not only achieve dosage control but also localize growth factors and preserve protein bioactivity. Physical entrapment usually involves premixing biomolecules with gelators and then directly stabilized in hydrogel scaffolds during the gelation process [93]. The entrapped biomolecules are usually released from the hydrogel via diffusion through the gel structure and liberation as the hydrogel dissolves [94]. Because there is no direct linkage between the biomolecule and hydrogel, their release rate is usually related to temperature, PH, and the components and construction of the hydrogel. To effectively control the release of TGF-β3, Deng et al. incorporated methacrylated HA into a poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA-PEG) hydrogel to form PDLLA-HA [42] (Figure 2(a)) and demonstrated that PDLLA-HA hydrogel constructs exhibited a continuous release of TGF-β3 for up to three weeks compared to the constructs without HA. In addition, these TGF-β3-preloaded constructs displayed dose-dependent enhancement of chondrogenic gene expression and glycosaminoglycan (GAG) production of human bone marrow mesenchymal stem cells (hBMSCs) both in vitro and in vivo. Similarly, Shen et al. demonstrated that photopolymerizable PDLLA hydrogel supported a long-term sustained release of TGF-β3 with the incorporation of graphene oxide (GO) nanosheets [97]. Alginate-based hydrogels represent promising microenvironments for cell culture and tissue engineering because of their injectability, biocompatibility, and biodegradability [98]. Moshaverinia et al. took advantage of the properties of alginates by designing a novel 3D drug delivery system loaded with a TGF-β1 ligand using an arginine-glycine-aspartic acid (RGD)-coupled alginate hydrogel for the microencapsulation of dental MSCs [99]. They found that TGF-β1 was consistently released from the alginate scaffold, and chondrogenic gene expression markers (Col II and SOX9) were observed by matrix staining after 4 weeks. This study indicates that an RGD-coupled alginate system can be used to encapsulate stem cells for cartilage regeneration. Gentile et al. developed a TGF-β1-loaded multilayer sodium alginate/gelatin hydrogel that was assembled by electrostatic attraction and hydrogen bonding [100]. Their results showed that this alginate-based scaffold consistently released TGF-β1 for up to 25 days and exhibited good cytocompatibility and chondrogenic promotion for bovine articular chondrocytes (BAC) it was adhered too.

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Figure 2

Various hydrogel-based growth factor delivery systems for cartilage regeneration. (a) Depiction of fabrication and culture of cell-loaded constructs. (A) represents the PDLLA/HA group, and (B) represents the PDLLA group; (b) schematic of TGF-β1 delivery from blue light-reactive MeGC hydrogels prepared by ionic conjugation or conjugation; (c) schematic diagram of the preparation and application of the trilayered fiber-reinforced and growth factor-loaded hydrogel construct: (A) fiber networks for the SD and B layers were fabricated by melt electrowriting; (B) the composite was constructed using the UV-assisted, stepwise infiltration, and crosslinking procedures; and (C) schematic illustration for the application of the trilayered composite scaffold in layer-specific osteochondral tissue induction and regeneration. Adapted with permission from Deng et al. [42], Choi et al. [95], and Qiao et al. [96].

Despite the simplicity of physical entrapment, the random diffusion of biomolecules is not conducive to the effective control of growth factor release. Compared with physical entrapment techniques, the chemical conjugation of growth factors to hydrogel scaffolds is a method that enhances the stability and persistence of growth factors [101]. As growth factors are either insoluble in or damaged by organic solvents, the immobilization of growth factors is generally performed via aqueous chemistry. Through chemical conjugation, growth factors can not only maintain their activity but also significantly extend their release over time, thereby resulting in better chondrogenesis. McCall et al. investigated the chondrogenic potency of TGF-β1-loaded PEG hydrogels on encapsulated human mesenchymal stem cells (hMSCs) [102]. In their study, TGF-β1 was first thiolated by a reaction with 2-iminothiolane and then loaded onto PEG hydrogels through a thiol-acrylate polymerization mechanism. When hMSCs were encapsulated in TGF-β1-loaded hydrogels, it was found that the hydrogel promoted chondrogenic differentiation of hMSCs at levels equal to or greater than those of the positive controls, where TGF-β1 was administered via the culture medium. A similar study reported a thiol-functionalized hyaluronic acid (HA-SH)-based hydrogel that covalently incorporated TGF-β1 was able to maintain the viability of the encapsulated MSCs and to promote the expression of chondrocyte ECM and chondrocytic genes; this improvement was positively correlated with TGF-β1 concentration [103]. When growth factors are chemically conjugated, they do not passively diffuse, and thus, their release occurs as the hydrogel degrades over its lifetime [104]. Therefore, the release rate of growth factors can be controlled more precisely by controlling the degradation rate of hydrogel scaffolds [105]. This can be achieved by causing the hydrogel to degrade in response to specific stimuli. Griffin et al. reported photodegradable polymerizable ortho-nitrobenzyl (o-NB) macromolecules with various functional groups at the benzylic position [106]. The authors conjugated TGF-β1 onto a PEG hydrogel and observed that the release of TGF-β1 could be controlled by light exposure, representing a promising method of temporally controlling drug release. Furthermore, photo-released TGF-β1 induced chondrogenic differentiation in human MSCs, similar to native TGF-β1. Choi et al. developed a strategy for sustained and slow TGF-β1 release using a blue light-reactive chitosan (MeGC)/collagen II hydrogel system, synthesized via covalent conjugation with an amine-to-sulfhydryl crosslinker, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). SMCC formed an amide bond with the primary amino groups on the chitosan backbone at the one end and a thioether bond with the cysteine residue on TGF-β1 at the other end. The controlled-release hydrogel system was shown to promote the viability and chondrogenic differentiation of adipose-derived stem cells (ADSCs) in vitro and cartilage regeneration of chondral defects in vivo [95] (Figure 2(b)).

6.2. Incorporation of Preformed Growth Factor-Loaded Delivery Systems

The dispersion of bioactive molecules in the matrix via immobilization on the hydrogel scaffold by covalent bonding or electrostatic interactions is a widely used method for creating a controlled delivery hydrogel. However, although large molecules can be physically entrapped in the mesh of a hydrogel, the attachment of small molecules is unpredictable, and thus, a labile linkage between these small molecules and the hydrogel network is desirable. An increasing number of studies have been conducted on the design of scaffolds incorporating preformed molecular-loaded delivery systems, such as polymer particles [107], rather than a direct combination of hydrogel and therapeutic biomolecules. Bioactive molecules are first loaded into a hydrogel precursor solution, which is subsequently fabricated into polymer particles through techniques such as batch emulsion [108], microfluidic emulsion [109], lithography [110], electrohydrodynamic spraying [111], and mechanical fragmentation [112, 113]. These polymer particles are then incorporated into a secondary hydrogel. This incorporation strategy can not only achieve better immobilization of small biomolecules but also temporarily separate the loaded biomolecules and the seeded cells that are also encapsulated in the secondary hydrogel, allowing a more precise stimulation of the preseeded cells. Ahearne et al. developed TGF-β3-loaded gelatin microspheres, mixing them with agarose hydrogels that were preseeded with chondroprogenitor cells to fabricate a growth factor-releasing hydrogel [114]. This allowed the slow release of growth factors from microspheres within the hydrogel and enabled the establishment and maintenance of a chondrogenic phenotype in seeded cells. In another study, PLGA-based porous microspheres were introduced as novel drug carriers by Reyes et al. [115]. In their study, PLGA microspheres were fabricated by gas foaming in an acidic aqueous solution. BMP-2 and TGF-β1 were pre-encapsulated in PLGA microspheres, which were subsequently dispersed in a matrix of segmented polyurethane (SPU) to form a bilayer scaffold system. The SPU-PLGA constructs released the growth factors in a well-regulated manner and induced rapid, good-quality osteochondral repair. Recently, Lin et al. developed an injectable methoxy poly(ethylene glycol)-poly(alanine) (mPA) hydrogel incorporating rat chondrocytes and TGF-β3-laden PLGA microspheres. This composite hydrogel system exhibited a sustained release of TGF-β3 and led to a significant upregulation of chondrocyte-specific genes and production of cartilage ECM components in the encapsulated MSCs [116]. In brief, incorporating preformed growth factor delivery systems in hydrogels containing chondroprogenitor cells represents promising new treatment options for CTE.

6.3. Multiple Growth Factor-Loaded Delivery Platforms

Chondrogenesis involves the activation of and interaction between many cellular signaling pathways, and it is impossible for a single factor to completely initiate the signaling pathways for cartilage regeneration. Therefore, efforts have been made to develop drug delivery systems that are loaded with multiple growth factors to increase their therapeutic effect on cartilage regeneration. For instance, previous studies have described the dual release of IGF-1 and TGF-β1 from hydrogel scaffolds [117, 118]. The release of IGF-1 and TGF-β1 can be controlled in a sequential manner and subsequently activated the expression of chondrogenic gene in MSCs. Han et al. developed a conically graded chitosan-gelatin hydrogel/PLGA scaffold to simultaneously deliver TGF-β1 and BMP-2 for cartilage-bone interface repair [119]. This scaffold exhibited spatially and temporally controlled release of TGF-β1 and BMP-2. The TGF-β1-loaded chitosan-gelatin hydrogel and BMP-2-loaded PLGA scaffold promoted chondrogenesis and osteogenesis, respectively. Although significant progress has been made in osteochondral tissue engineering, successfully reconstructing tissues with compositions, structures, and functional properties that are similar to those of native tissues remains a challenge. Inspired by the gradient of ECM composition and fibrous collagen structure in native osteochondral tissue, Qian et al. produced poly(ε-caprolactone) and polyethylene glycol (PCEC) 3D-stratified scaffolds with superficial cartilage, deep cartilage, and subchondral bone layers, which were filled with methacrylamide hydrogels (GelMA) containing MSCs and the regional-specific growth factors BMP-7, TGF-1, and BMP-2 [96] (Figure 2(c)). The complex-induced chondrogenic and osteoblastic differentiation in MSCs promoted the expression of cellular phenotypes and matrix accumulation profiles similar to native tissues in vitro. In vivo experiments further confirmed that the fiber-reinforced and growth factor-loaded trilaminar hydrogel structure had a positive effect on osteochondral regeneration.

6.4. Platelet-Rich Plasma-Loaded Delivery Platforms

Platelet-rich plasma (PRP), a concentration of platelets, is a reservoir of multiple growth factors, such as isoforms of TGF, IGF, and platelet-derived growth factor (PDGF), and has been demonstrated to stimulate the migration, proliferation, and chondrogenic differentiation of stem cells [121]. Owing to its abundant therapeutic potential, PRP presents an alternative approach for the development of controlled-release systems [122]. Lu et al. developed a PRP-loaded genipin-gelatin/hyaluronic acid/fucoidan (GP-GLT/HA/FD) hydrogel by adding lyophilized PRP powder into a GP-GLT/HA/FD mixture before gelation, and this controlled delivery system exhibited a sustained release of PDGF instead of the burst release associated with traditional PRP gels [123]. The PRP-loaded GP-GLT/HA/FD hydrogel showed a reduced loss of chondrocytes and decreased lesion formation in vivo, indicating potential as an osteoarthritis therapy. To overcome the burst release of growth factors in traditional PRP gels, Liu et al. proposed photocrosslinkable PRP hydrogel glue (HNPRP) based on a photoinduced imine crosslinking (PIC) reaction [124] (Figure 3(a)). Exposure to light causes o-NB alcohol-modified hyaluronic acid (HA-NB) in a PRP hydrogel to form aldehyde groups, which subsequently react with the amino groups distributed on the fibrinogen of PRP, generating a hydrogel in situ. The release of PDGF, TGF-β, and FGF from this HNPRP hydrogel was approximately linear for 14 days, whereas an obvious burst release was observed in the traditional thrombin-activated PRP gel after 2 days. Functional tests confirmed that the system promoted the migration and proliferation of both BMSCs and chondrocytes and achieved better cartilage regeneration than thrombin-activated PRP gel. Platelet lysates (PLs) are derivatives of PRP, where the platelets of PRP are lysed to release their protein content [123]. Jooybar et al. designed a novel delivery system called the platelet lysate-incorporated hyaluronic acid-tyramine (HA-TA-PL) hydrogel via enzymatic crosslinking, and it showed a promotive effect on the viability, proliferation, and chondrogenesis of hMSCs [124] (Figure 3(b)). An overview of the hydrogels used as growth factor delivery platforms for cartilage regeneration is summarized in Table 1.

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Figure 3

Various PRP-loaded hydrogel systems for cartilage regeneration. (a) Characterization of HNPRP hydrogel: (A) schematic illustration of the gelling mechanism of HNPRP hydrogel and its covalent adhesiveness and integration to native cartilage; (B) rheological property of HNPRP hydrogel precursor solution (40 mg/mL HA-NB saline solution blended with the same volume of extracted rabbit blood PRP) under light irradiation at 37°C; and (C) SEM images of freeze-dried HNPRP hydrogel glue and thrombin-activated PRP gel; (b) preparation of platelet lysate-incorporated HA-TA-PL hydrogels and its promotive effect on the viability, proliferation, and chondrogenesis of hMSCs. Adapted with permission from Liu et al. [123] and Jooybar et al. [23].

7. Gene Delivery Platform using Hydrogel Scaffold for Cartilage Regeneration

Growth factor-incorporated hydrogel scaffolds have been widely investigated as drug delivery systems. However, the therapeutic efficacy of the direct delivery of these growth factors is often hampered by their shortcomings, such as their transient action, short half-life, and need for high concentrations to be effective [126]. Gene therapy is considered an alternative approach that can control the expression of growth factors by delivering genetic material encoding the desired protein to the target site [127]. However, the use of genes is still limited by their low transfection efficiency, rapid degradation, and short-term transgene expression levels [128]. Incorporating genes into hydrogels may protect DNA against enzymatic degradation and increase transfection efficiency [129] (Figure 4). Therefore, gene-loaded hydrogel systems may serve as an attractive alternative in CTE.

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Figure 4

Preparation and application of rAAV-FLAG-hSOX9/PEO-PPO-PEO hydrogel for the treatment of cartilage defects. (a) Structure of the PEO-PPO-PEO (PF127) block copolymer; (b) thermosensitive characteristics of the copolymer (liquid form at 4°C and solid form at 37°C); (c) flowchart of generation of the rAAV/hydrogel systems for the controlled release of rAAV with implantation in knee full-thickness chondral defects in minipigs following microfracture. The accumulated controlled-release pattern of rAAV from PF127 is presented relative to free rAAV; (d) intraoperative view of the full-thickness chondral defect creation and treatment with microfracture augmented with in situ gelation of the rAAV/hydrogels. Adapted with permission from Madry et al. [129].

7.1. Viral Vector-Based Gene Delivery Platforms

Successful gene therapy requires optimal gene delivery. Currently, viral and nonviral vectors are the most commonly used gene delivery vectors [130, 131]. Using viral vectors generally involves direct administration of the vectors, which allows for the controlled and minimally invasive delivery of the genes in a spatiotemporally precise manner, reducing the possible spread and loss of gene products [132]. Madry et al. incorporated a recombinant adeno-associated virus (rAAV) vector in a thermosensitive hydrogel based on poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) poloxamers. The rAAV vector overexpressed the chondrogenic SOX9 transcription factor, and the hydrogel system controlled the release of the virus vector in a full-thickness chondral defect minipig model [129]. Comprehensive analyses indicated that the rAAV vector system significantly improved cartilage regeneration and protected the subchondral bone plate from early bone loss. Maihöfer et al. reported the effect of an IGF-1-coding rAAV vector-laden alginate hydrogel (IGF-1/AlgPH155) in the treatment of full-thickness chondral defects [133]. Compared with the control (lacZ/AlgPH155) treatment, IGF-1/AlgPH155 consistently overexpressed IGF-1 for one year and thereby achieved an improvement in cartilage repair and a reduction in perifocal osteoarthritis and inflammation. In CTE, relatively little attention has been paid to the zonal organization of neocartilage tissue. To generate different types of neocartilage constructs, Weibenberger et al. fabricated a series of type I collagen hydrogels containing human bone marrow MSCs transfected with SOX9-, TGF-β1-, or BMP-2-encoding adenoviral vectors [134]. MSC chondrogenesis was detected in all hydrogels, but the expression of alkaline phosphatase (ALP) and Col-X demonstrated the three hydrogels had produced different types of neocartilage with varying levels of cartilage hypertrophy among them (BMP2 > TGFB1 > SOX9), indicating that this technology may be used for the regeneration of specific zones of native cartilage.

7.2. Nonviral Vector-Based Gene Delivery Platforms

The nonviral vector strategy requires the extraction of cells that were previously transfected with a gene vector, which are then introduced to the site of interest. Compared with viral-based gene delivery systems, nonviral systems are often considered to have advantages for in vivo use in cartilage regeneration because of their security, low immunogenicity, ease of operation, and relatively low cost [135, 136]. Nonviral gene therapies for CTE generally involve attaching chondrocytes or MSCs transfected with the desired gene for encoding chondrogenic growth factors onto hydrogel scaffolds. Madry et al. reported that the incorporation of human IGF-1 cDNA-transfected articular chondrocytes into alginate hydrogels enhanced the therapeutic effect of the hydrogel on full-thickness cartilage injuries in rabbits [137]. Lu et al. reported the use of gene therapy to achieve temporally controlled delivery of chondrogenic growth factors [138]. The authors developed a local gene delivery system using a porous chitosan scaffold embedded with hybrid HA/chitosan/pDNA nanoparticles that carry plasmids encoding TGF-β1. In vitro, the hydrogel sustained the release of the plasmids for more than 120 days. In addition, the development of chondrocytes and surrounding ECM structures was observed in the chitosan scaffolds. Gonzalez-Fernandez et al. performed gene delivery for osteochondral regeneration using TGF-β3 and BMP-2 in an MSC-loaded alginate hydrogel [139]. Their results showed that the genes were effectively delivered to the MSCs within the alginate hydrogels without any cytotoxicity. Furthermore, the delivery of TGF-β3 and BMP-2 significantly increased the sGAG and collagen production of the MSCs, especially when they were delivered in combination. The simultaneous regeneration of bone and cartilage is important for osteochondral defect repair but difficult to achieve in tissue regeneration [140]. Spatial delivery of genes using multiphase scaffolds for spatial guidance of cellular processes is a promising approach to facilitate the reconstruction of complex tissue structures. An effective strategy for the simultaneous regeneration of bone and cartilage using a gene delivery therapy was reported by Chen et al. [141]. The authors developed a bilayered scaffold consisting of a plasmid BMP-2-loaded hydroxyapatite/chitosan-gelatin scaffold for the osteogenic layer, and a plasmid TGF-β1-loaded chitosan-gelatin scaffold for the chondrogenic layer. MSCs in this bilayered scaffold were very proliferative, with TGF-β1 and BMP-2 proteins being highly expressed in their corresponding layer. Moreover, an osteochondral tissue composite was generated in vitro, and the osteochondral defect was repaired in vivo using this bilayered scaffold. This approach of spatially controlled gene delivery represents a promising strategy for osteochondral tissue engineering. An overview of the hydrogels used as gene delivery platforms for cartilage regeneration is summarized in Table 2.

8. Conclusions

Homeostasis and regeneration of cartilage tissue are strictly controlled by several signaling biomolecules and the interactions between cells and the ECM. The use of hydrogels as biomolecule delivery platforms is a promising strategy for improving the current treatments of CTE. This strategy can introduce appropriate levels of therapeutic biomolecules into target locations, and the specific dosage, spatial distribution, and temporal sequence can be precisely controlled. Moreover, hydrogel delivery platforms are highly tunable and can be designed to deliver biomolecules in specific ways by varying the hydrogel composition, crosslinking density, and degradation kinetics.

9. Future Perspectives

At present, researchers are gradually realizing that some biomolecules may only be suitable for certain delivery platforms, and the biocompatibility, activity, and stability of biomolecules are also key factors that determine the success of delivery platforms. Therefore, future efforts should be undertaken to identify the underlying mechanisms of biomolecule-to-platform interactions, thus improving the optimization of drug delivery platforms. Secondly, the degradation of hydrogels might impair their mechanical stability and long-term therapeutic effect; therefore, the incorporation of exogenous cells, such as MSCs, could potentially replace the degrading scaffolds with regenerated tissue. In addition, to successfully transfer hydrogel drug delivery systems from the laboratory to the market, further development is needed to design hydrogels with sufficient stiffness, minimal tissue response, and proper release and degradation profiles. Moreover, modular tissue assembly is a relatively unexplored strategy for stepwise biofabrication of 3D tissue constructs using cell-seeded scaffolds and preformed tissue units. The modular assembly enables the development of individually optimized and interchangeable modules that can jointly meet the requirements of functional cartilage regeneration scaffolds. Finally, noninvasive or minimally invasive diagnostic methods should be combined with the next generation of CTE, as the disease status and the therapeutic effect of the treatment could be observed and assessed in real time. Currently, the diagnosis of cartilage defects is mostly based on the results of imaging techniques, including X-ray, computerized tomography, magnetic resonance imaging, and ultrasound, but all of them have certain limitations. Thanks to the rapid development of artificial intelligence (AI) technology, its algorithm has been used to increase the accuracy of feature images. Moreover, the development of computational models and in silico simulations (such as the finite element method, computational fluid dynamics, or finite volume method) has enabled the rapid production of predictive models. It is reasonable to imagine that the combination of imaging techniques and these simulations may provide tissue engineers and physicians with timely, dynamic predictive models that can be used in the next generation of CTE.

Data Availability

No data were used to support the findings of the study.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Jingyan Guan and Jingwei Feng contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant nos. 81601702, 81671931, 81701920, 81801933, and 82102350).

References

J. Galle, A. Bader, P. Hepp et al., “Mesenchymal stem cells in cartilage repair: state of the art and methods to monitor cell growth, differentiation and cartilage regeneration,” Current Medicinal Chemistry, vol. 17, pp. 2274–2291, 2010.
View at: Publisher Site | Google Scholar
A. P. Hollander, S. C. Dickinson, and W. Kafienah, “Stem cells and cartilage development: complexities of a simple tissue,” Stem Cells, vol. 28, pp. 1992–1996, 2010.
View at: Publisher Site | Google Scholar
N. Nakayama, A. Pothiawala, J. Y. Lee et al., “Human pluripotent stem cell-derived chondroprogenitors for cartilage tissue engineering,” Cellular and Molecular Life Sciences, vol. 77, pp. 2543–2563, 2020.
View at: Publisher Site | Google Scholar
H. Le, W. Xu, X. Zhuang, F. Chang, Y. Wang, and J. Ding, “Mesenchymal stem cells for cartilage regeneration,” Journal of Tissue Engineering, vol. 11, Article ID 204173142094383, 2020.
View at: Publisher Site | Google Scholar
L. Kock, C. C. van Donkelaar, and K. Ito, “Tissue engineering of functional articular cartilage: the current status,” Cell and Tissue Research, vol. 347, pp. 613–627, 2012.
View at: Publisher Site | Google Scholar
A. Rahmani Del Bakhshayesh, S. Babaie, H. Tayefi Nasrabadi, N. Asadi, A. Akbarzadeh, and A. Abedelahi, “An overview of various treatment strategies, especially tissue engineering for damaged articular cartilage,” Artificial Cells, Nanomedicine, and Biotechnology, vol. 48, pp. 1089–1104, 2020.
View at: Publisher Site | Google Scholar
J. Xu, E. Feng, and J. Song, “Bioorthogonally cross-linked hydrogel network with precisely controlled disintegration time over a broad range,” Journal of the American Chemical Society, vol. 136, pp. 4105–4108, 2014.
View at: Publisher Site | Google Scholar
K. T. Shalumon and J. P. Chen, “Scaffold-based drug delivery for cartilage tissue regeneration,” Current Pharmaceutical Design, vol. 21, pp. 1979–1990, 2015.
View at: Publisher Site | Google Scholar
T. Garg, O. Singh, S. Arora, and R. S. R. Murthy, “Scaffold: a novel carrier for cell and drug delivery,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 29, pp. 1–63, 2012.
View at: Publisher Site | Google Scholar
A. C. Lima, H. Ferreira, R. L. Reis, and N. M. Neves, “Biodegradable polymers: an update on drug delivery in bone and cartilage diseases,” Expert Opinion on Drug Delivery, vol. 16, pp. 795–813, 2019.
View at: Publisher Site | Google Scholar
M. Vázquez González and I. Willner, “Stimuli responsive biomolecule based hydrogels and their applications,” Angewandte Chemie International Edition, vol. 59, pp. 15342–15377, 2020.
View at: Publisher Site | Google Scholar
H. M. El-Husseiny, E. A. Mady, L. Hamabe et al., “Smart/stimuli-responsive hydrogels: cutting-edge platforms for tissue engineering and other biomedical applications,” Materials Today Bio, vol. 13, Article ID 100186, 2022.
View at: Publisher Site | Google Scholar
H. M. El-Husseiny, E. A. Mady, W. A. El-Dakroury et al., “Smart/stimuli-responsive hydrogels: state-of-the-art platforms for bone tissue engineering,” Applied Materials Today, Article ID 101560, 2022.
View at: Publisher Site | Google Scholar
A. Roy, K. Manna, and S. Pal, “Recent advances in various stimuli-responsive hydrogels: from synthetic designs to emerging healthcare applications,” Materials Chemistry Frontiers, vol. 6, pp. 2338–2385, 2022.
View at: Publisher Site | Google Scholar
J. Hoque, N. Sangaj, and S. Varghese, “Stimuli-responsive supramolecular hydrogels and their applications in regenerative medicine,” Macromolecular Bioscience, vol. 19, Article ID e1800259, 2019.
View at: Publisher Site | Google Scholar
T. Re'Em, Y. Kaminer-Israeli, E. Ruvinov, and S. Cohen, “Chondrogenesis of hMSC in affinity-bound TGF-beta scaffolds,” Biomaterials, vol. 33, pp. 751–761, 2012.
View at: Publisher Site | Google Scholar
J. A. Simson, I. A. Strehin, Q. Lu, M. O. Uy, and J. H. Elisseeff, “An adhesive bone marrow scaffold and bone morphogenetic-2 protein carrier for cartilage tissue engineering,” Biomacromolecules, vol. 14, pp. 637–643, 2013.
View at: Publisher Site | Google Scholar
E. Saygili, E. Kaya, E. Ilhan-Ayisigi et al., “An alginate-poly(acrylamide) hydrogel with TGF-β3 loaded nanoparticles for cartilage repair: biodegradability, biocompatibility and protein adsorption,” International Journal of Biological Macromolecules, vol. 172, pp. 381–393, 2021.
View at: Publisher Site | Google Scholar
Z. Mahmoudi, J. Mohammadnejad, S. Razavi Bazaz et al., “Promoted Chondrogenesis of hMCSs with Controlled Release of TGF-Β3 via Microfluidics Synthesized Alginate Nanogels,” Carbohydrate Polymers, vol. 229, Article ID 115551, 2020.
View at: Publisher Site | Google Scholar
X. Xu, A. K. Jha, R. L. Duncan, and X. Jia, “Heparin-decorated, hyaluronic acid-based hydrogel particles for the controlled release of bone morphogenetic protein 2,” Acta Biomaterialia, vol. 7, pp. 3050–3059, 2011.
View at: Publisher Site | Google Scholar
L. Bian, D. Y. Zhai, E. Tous, R. Rai, R. L. Mauck, and J. A. Burdick, “Enhanced MSC chondrogenesis following delivery of TGF-β3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo,” Biomaterials, vol. 32, pp. 6425–6434, 2011.
View at: Publisher Site | Google Scholar
H. Liu, Y. Rui, J. Liu, F. Gao, and Y. Jin, “Hyaluronic acid hydrogel encapsulated BMP-14-modified ADSCs accelerate cartilage defect repair in rabbits,” Journal of Orthopaedic Surgery and Research, vol. 16, no. 1, p. 657, 2021.
View at: Publisher Site | Google Scholar
I. Catelas, J. F. Dwyer, and S. Helgerson, “Controlled release of bioactive transforming growth factor beta-1 from fibrin gels in vitro,” Tissue Engineering Part C Methods, vol. 14, pp. 119–128, 2008.
View at: Publisher Site | Google Scholar
B. Hashemibeni, A. Valiani, M. Esmaeli, M. Kazemi, M. Aliakbari, and F. G. Iranpour, Iran J Basic Med Sci, vol. 21, pp. 212–218, 2018.
View at: Publisher Site
Q. Yang, B. H. Teng, L. N. Wang et al., “Silk fibroin/cartilage extracellular matrix scaffolds with sequential delivery of TGF-β3 for chondrogenic differentiation of adipose-derived stem cells,” International Journal of Nanomedicine, vol. 12, pp. 6721–6733, 2017.
View at: Publisher Site | Google Scholar
D. Seliktar, “Designing cell-compatible hydrogels for biomedical applications,” Science, vol. 336, pp. 1124–1128, 2012.
View at: Publisher Site | Google Scholar
K. L. Spiller, Y. Liu, J. L. Holloway et al., “A novel method for the direct fabrication of growth factor-loaded microspheres within porous nondegradable hydrogels: controlled release for cartilage tissue engineering,” Journal of Controlled Release, vol. 157, pp. 39–45, 2012.
View at: Publisher Site | Google Scholar
J. S. Park, H. N. Yang, D. G. Woo, S. Y. Jeon, and K. H. Park, “SOX9 gene plus heparinized TGF-β 3 coated dexamethasone loaded PLGA microspheres for inducement of chondrogenesis of hMSCs,” Biomaterials, vol. 33, pp. 7151–7163, 2012.
View at: Publisher Site | Google Scholar
B. C. Geiger, S. Wang, R. F. Padera, A. J. Grodzinsky, and P. T. Hammond, “Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis,” Science Translational Medicine, vol. 10, 2018.
View at: Publisher Site | Google Scholar
J. S. Park, D. G. Woo, H. N. Yang et al., “Chondrogenesis of human mesenchymal stem cells encapsulated in a hydrogel construct: neocartilage formation in animal models as both mice and rabbits,” Journal of Biomedical Materials Research Part A, vol. 92, no. 3, pp. 988–996, 2010.
View at: Publisher Site | Google Scholar
J. L. Holloway, H. Ma, R. Rai, and J. A. Burdick, “Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation,” Journal of Controlled Release, vol. 191, pp. 63–70, 2014.
View at: Publisher Site | Google Scholar
R. Censi, T. Vermonden, H. Deschout et al., “Photopolymerized thermosensitive poly(HPMAlactate)-PEG-based hydrogels: effect of network design on mechanical properties, degradation, and release behavior,” Biomacromolecules, vol. 11, pp. 2143–2151, 2010.
View at: Publisher Site | Google Scholar
K. Chawla, T. B. Yu, L. Stutts, M. Yen, and Z. Guan, “Modulation of chondrocyte behavior through tailoring functional synthetic saccharide-peptide hydrogels,” Biomaterials, vol. 33, pp. 6052–6060, 2012.
View at: Publisher Site | Google Scholar
C. Vasile, D. Pamfil, E. Stoleru, and M. Baican, “New developments in medical applications of hybrid hydrogels containing natural polymers,” Molecules, vol. 25, p. 1539, 2020.
View at: Publisher Site | Google Scholar
N. Khalilijafarabad, A. Behnamghader, M. T. Khorasani, and M. Mozafari, “Platelet rich plasma hyaluronic acid/chondrotin sulfate/carboxymethyl chitosan hydrogel for cartilage regeneration,” Biotechnology and Applied Biochemistry, vol. 69, no. 2, pp. 534–547, 2021.
View at: Publisher Site | Google Scholar
C. Levinson, E. Cavalli, B. von Rechenberg, M. Zenobi-Wong, and S. E. Darwiche, “Combination of a Collagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for Cartilage Regeneration: A Proof of Concept in an Ovine Model,” CARTILAGE, vol. 13, no. 2_suppl, Article ID 765194525, pp. 636S–649S, 2021.
View at: Publisher Site | Google Scholar
J. Lin, L. Wang, J. Lin, and Q. Liu, “Dual delivery of TGF-β3 and ghrelin in microsphere/hydrogel systems for cartilage regeneration,” Molecules, vol. 26, p. 5732, 2021.
View at: Publisher Site | Google Scholar
Y. Xu, Z. Wang, Y. Hua et al., “Photocrosslinked natural hydrogel composed of hyaluronic acid and gelatin enhances cartilage regeneration of decellularized trachea matrix,” Materials Science and Engineering: C, vol. 120, Article ID 111628, 2021.
View at: Publisher Site | Google Scholar
M. U. Aslam Khan, S. I. Abd Razak, W. S. Al Arjan et al., “Recent advances in biopolymeric composite materials for tissue engineering and regenerative medicines: a review,” Molecules, vol. 26, p. 619, 2021.
View at: Publisher Site | Google Scholar
J. Yoo and Y. Y. Won, “Phenomenology of the initial burst release of drugs from PLGA microparticles,” ACS Biomaterials Science & Engineering, vol. 6, pp. 6053–6062, 2020.
View at: Publisher Site | Google Scholar
Y. Deng, A. X. Sun, K. J. Overholt et al., “Enhancing chondrogenesis and mechanical strength retention in physiologically relevant hydrogels with incorporation of hyaluronic acid and direct loading of TGF-β,” Acta Biomaterialia, vol. 83, pp. 167–176, 2019.
View at: Publisher Site | Google Scholar
F. J. O'Brien, B. A. Harley, I. V. Yannas, and L. J. Gibson, “The effect of pore size on cell adhesion in collagen-GAG scaffolds,” Biomaterials, vol. 26, pp. 433–441, 2005.
View at: Publisher Site | Google Scholar
J. J. Campbell, A. Husmann, R. D. Hume, C. J. Watson, and R. E. Cameron, “Development of Three-Dimensional Collagen Scaffolds with Controlled Architecture for Cell Migration Studies Using Breast Cancer Cell Lines,” Biomaterials, vol. 114, pp. 34–43, 2017.
View at: Publisher Site | Google Scholar
A. Al-Abboodi, J. Fu, P. M. Doran, T. T. Y. Tan, and P. P. Y. Chan, “Injectable 3D hydrogel scaffold with tailorable porosity post-implantation,” Advanced Healthcare Materials, vol. 3, pp. 725–736, 2014.
View at: Publisher Site | Google Scholar
M. Yagi, M. Mizuno, R. Fujisawa et al., “Optimal pore size of honeycomb polylactic acid films for in vitro cartilage formation by synovial mesenchymal stem cells,” Stem Cells International, vol. 2021, Article ID 9239728, pp. 1–9, 2021.
View at: Publisher Site | Google Scholar
Q. Zhang, H. Lu, N. Kawazoe, and G. Chen, “Pore size effect of collagen scaffolds on cartilage regeneration,” Acta Biomaterialia, vol. 10, pp. 2005–2013, 2014.
View at: Publisher Site | Google Scholar
M. M. Nava, L. Draghi, C. Giordano, and R. Pietrabissa, “The effect of scaffold pore size in cartilage tissue engineering,” Journal of Applied Biomaterials & Functional Materials, vol. 14, pp. e223–e229, 2016.
View at: Publisher Site | Google Scholar
L. Zeng, Y. Yao, D. a. Wang, and X. Chen, “Effect of microcavitary alginate hydrogel with different pore sizes on chondrocyte culture for cartilage tissue engineering,” Materials Science and Engineering: C, vol. 34, pp. 168–175, 2014.
View at: Publisher Site | Google Scholar
S. Yamane, N. Iwasaki, Y. Kasahara et al., “Effect of pore size onin vitro cartilage formation using chitosan-based hyaluronic acid hybrid polymer fibers,” Journal of Biomedical Materials Research Part A, vol. 81A, pp. 586–593, 2007.
View at: Publisher Site | Google Scholar
T. B. F. Woodfield, C. V. Blitterswijk, J. D. Wijn, T. J. Sims, A. P. Hollander, and J. Riesle, “Polymer scaffolds fabricated with pore-size gradients as a model for studying the zonal organization within tissue-engineered cartilage constructs,” Tissue Engineering, vol. 11, no. 9-10, pp. 1297–1311, 2005.
View at: Publisher Site | Google Scholar
S. M. Lien, L. Y. Ko, and T. J. Huang, “Effect of pore size on ECM secretion and cell growth in gelatin scaffold for articular cartilage tissue engineering,” Acta Biomaterialia, vol. 5, pp. 670–679, 2009.
View at: Publisher Site | Google Scholar
J. Berger, M. Reist, J. M. Mayer, O. Felt, N. A. Peppas, and R. Gurny, “Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 57, pp. 19–34, 2004.
View at: Publisher Site | Google Scholar
C. K. Kuo and P. X. Ma, “Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: part 1. Structure, gelation rate and mechanical properties,” Biomaterials, vol. 22, pp. 511–521, 2001.
View at: Publisher Site | Google Scholar
H. Park, M. H. Kim, Y. I. Yoon, and W. H. Park, “One-pot Synthesis of Injectable Methylcellulose Hydrogel Containing Calcium Phosphate Nanoparticles,” Carbohydr Polym, vol. 157, pp. 775–783, 2017.
View at: Publisher Site | Google Scholar
X. Jiang, N. Xiang, H. Zhang, Y. Sun, Z. Lin, and L. Hou, “Preparation and Characterization of Poly(vinyl Alcohol)/sodium Alginate Hydrogel with High Toughness and Electric Conductivity,” Carbohydr Polym, vol. 186, pp. 377–383, 2018.
View at: Publisher Site | Google Scholar
H. Li, P. Yang, P. Pageni, and C. Tang, “Recent advances in metal-containing polymer hydrogels,” Macromolecular Rapid Communications, vol. 38, Article ID 1700109, 2017.
View at: Publisher Site | Google Scholar
H. Hofmeier, R. Hoogenboom, M. E. L. Wouters, and U. S. Schubert, “High molecular weight supramolecular polymers containing both terpyridine metal complexes and ureidopyrimidinone quadruple hydrogen-bonding units in the main chain,” Journal of the American Chemical Society, vol. 127, pp. 2913–2921, 2005.
View at: Publisher Site | Google Scholar
J. Berger, M. Reist, J. M. Mayer, O. Felt, and R. Gurny, “Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 57, pp. 35–52, 2004.
View at: Publisher Site | Google Scholar
L. S. Moreira Teixeira, J. Feijen, C. A. van Blitterswijk, P. J. Dijkstra, and M. Karperien, “Enzyme-catalyzed crosslinkable hydrogels: emerging strategies for tissue engineering,” Biomaterials, vol. 33, pp. 1281–1290, 2012.
View at: Publisher Site | Google Scholar
K. S. Kim, S. J. Park, J. A. Yang et al., “Injectable hyaluronic acid–tyramine hydrogels for the treatment of rheumatoid arthritis,” Acta Biomaterialia, vol. 7, pp. 666–674, 2011.
View at: Publisher Site | Google Scholar
I. Mironi-Harpaz, D. Y. Wang, S. Venkatraman, and D. Seliktar, “Photopolymerization of cell-encapsulating hydrogels: crosslinking efficiency versus cytotoxicity,” Acta Biomaterialia, vol. 8, pp. 1838–1848, 2012.
View at: Publisher Site | Google Scholar
S. Yigit, R. Sanyal, and A. Sanyal, “Fabrication and functionalization of hydrogels through “click” chemistry,” Chemistry - An Asian Journal, vol. 6, pp. 2648–2659, 2011.
View at: Publisher Site | Google Scholar
W. Hu, Z. Wang, Y. Xiao, S. Zhang, and J. Wang, “Advances in crosslinking strategies of biomedical hydrogels,” Biomaterials Science, vol. 7, pp. 843–855, 2019.
View at: Publisher Site | Google Scholar
L. Arnfast, C. G. Madsen, L. Jorgensen, and S. Baldursdottir, “Design and processing of nanogels as delivery systems for peptides and proteins,” Therapeutic Delivery, vol. 5, pp. 691–708, 2014.
View at: Publisher Site | Google Scholar
M. Zhong, Y. T. Liu, X. Y. Liu et al., “Dually cross-linked single network poly(acrylic acid) hydrogels with superior mechanical properties and water absorbency,” Soft Matter, vol. 12, pp. 5420–5428, 2016.
View at: Publisher Site | Google Scholar
S. H. Lee and H. Shin, “Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering,” Advanced Drug Delivery Reviews, vol. 59, pp. 339–359, 2007.
View at: Publisher Site | Google Scholar
T. Michigami, “Current understanding on the molecular basis of chondrogenesis, Clinical pediatric endocrinology: case reports and clinical investigations,” Official Journal of the Japanese Society for Pediatric Endocrinology, vol. 23, no. 1, pp. 1–8, 2014.
View at: Publisher Site | Google Scholar
E. Kozhemyakina, A. B. Lassar, and E. Zelzer, “A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation,” Development, vol. 142, pp. 817–831, 2015.
View at: Publisher Site | Google Scholar
E. Augustyniak, T. Trzeciak, M. Richter, J. Kaczmarczyk, and W. Suchorska, “The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration,” International Orthopaedics, vol. 39, pp. 995–1003, 2015.
View at: Publisher Site | Google Scholar
H. Kwon, N. K. Paschos, J. C. Hu, and K. Athanasiou, “Articular cartilage tissue engineering: the role of signaling molecules,” Cellular and Molecular Life Sciences, vol. 73, pp. 1173–1194, 2016.
View at: Publisher Site | Google Scholar
D. Horbelt, A. Denkis, and P. Knaus, “A portrait of Transforming Growth Factor beta superfamily signalling: background matters,” The International Journal of Biochemistry & Cell Biology, vol. 44, pp. 469–474, 2012.
View at: Publisher Site | Google Scholar
E. Music, T. J. Klein, W. B. Lott, and M. R. Doran, “Transforming growth factor-beta stimulates human bone marrow-derived mesenchymal stem/stromal cell chondrogenesis more so than kartogenin,” Scientific Reports, vol. 10, no. 1, p. 8340, 2020.
View at: Publisher Site | Google Scholar
M. B. Mueller, M. Fischer, J. Zellner et al., “Hypertrophy in mesenchymal stem cell chondrogenesis: effect of TGF-beta isoforms and chondrogenic conditioning,” Cells Tissues Organs, vol. 192, pp. 158–166, 2010.
View at: Publisher Site | Google Scholar
C. Vinatier, D. Mrugala, C. Jorgensen, J. Guicheux, and D. Noel, “Cartilage engineering: a crucial combination of cells, biomaterials and biofactors,” Trends in Biotechnology, vol. 27, pp. 307–314, 2009.
View at: Publisher Site | Google Scholar
M. Ochi, K. Kawasaki, H. Kataoka, Y. Uchio, and H. Nishi, “AG-041R, a gastrin/CCK-B antagonist, stimulates chondrocyte proliferation and metabolism in vitro,” Biochemical and Biophysical Research Communications, vol. 283, pp. 1118–1123, 2001.
View at: Publisher Site | Google Scholar
T. Suzuki, K. Bessho, K. Fujimura, Y. Okubo, N. Segami, and T. Iizuka, “Regeneration of defects in the articular cartilage in rabbit temporomandibular joints by bone morphogenetic protein-2,” British Journal of Oral and Maxillofacial Surgery, vol. 40, pp. 201–206, 2002.
View at: Publisher Site | Google Scholar
R. Mihelic, M. Pecina, M. Jelic et al., “Bone morphogenetic protein-7 (osteogenic protein-1) promotes tendon graft integration in anterior cruciate ligament reconstruction in sheep,” The American Journal of Sports Medicine, vol. 32, pp. 1619–1625, 2004.
View at: Publisher Site | Google Scholar
M. P. Lutolf, F. E. Weber, H. G. Schmoekel et al., “Repair of bone defects using synthetic mimetics of collagenous extracellular matrices,” Nature Biotechnology, vol. 21, pp. 513–518, 2003.
View at: Publisher Site | Google Scholar
C. Phornphutkul, K. Y. Wu, X. Yang, Q. Chen, and P. A. Gruppuso, “Insulin-like growth factor-I signaling is modified during chondrocyte differentiation,” Journal of Endocrinology, vol. 183, pp. 477–486, 2004.
View at: Publisher Site | Google Scholar
S. J. Oh, K. U. Choi, S. W. Choi et al., “Comparative analysis of adipose-derived stromal cells and their secretome for auricular cartilage regeneration,” Stem Cells International, vol. 2020, Article ID 8595940, pp. 1–8, 2020.
View at: Publisher Site | Google Scholar
L. Longobardi, L. O'Rear, S. Aakula et al., “Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling,” Journal of Bone and Mineral Research, vol. 21, pp. 626–636, 2005.
View at: Publisher Site | Google Scholar
A. Beenken and M. Mohammadi, “The FGF family: biology, pathophysiology and therapy,” Nature Reviews Drug Discovery, vol. 8, pp. 235–253, 2009.
View at: Publisher Site | Google Scholar
S. L. Chia, Y. Sawaji, A. Burleigh et al., “Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis,” Arthritis & Rheumatism, vol. 60, pp. 2019–2027, 2009.
View at: Publisher Site | Google Scholar
M. B. Ellman, H. S. An, P. Muddasani, and H. J. Im, “Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis,” Gene, vol. 420, pp. 82–89, 2008.
View at: Publisher Site | Google Scholar
A. A. Stewart, C. R. Byron, H. Pondenis, and M. C. Stewart, “Effect of fibroblast growth factor-2 on equine mesenchymal stem cell monolayer expansion and chondrogenesis,” American Journal of Veterinary Research, vol. 68, pp. 941–945, 2007.
View at: Publisher Site | Google Scholar
E. E. Moore, A. M. Bendele, D. L. Thompson et al., “Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis,” Osteoarthritis and Cartilage, vol. 13, pp. 623–631, 2005.
View at: Publisher Site | Google Scholar
S. Murakami, M. Kan, W. L. Mckeehan, and B. de Crombrugghe, “Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway,” Proceedings of the National Academy of Sciences, vol. 97, pp. 1113–1118, 2000.
View at: Publisher Site | Google Scholar
R. Censi, P. Di Martino, T. Vermonden, and W. E. Hennink, “Hydrogels for protein delivery in tissue engineering,” Journal of Controlled Release, vol. 161, pp. 680–692, 2012.
View at: Publisher Site | Google Scholar
B. Balakrishnan and R. Banerjee, “Biopolymer-based hydrogels for cartilage tissue engineering,” Chemistry Review, vol. 111, pp. 4453–4474, 2011.
View at: Publisher Site | Google Scholar
L. Cao and D. J. Mooney, “Spatiotemporal control over growth factor signaling for therapeutic neovascularization,” Advanced Drug Delivery Reviews, vol. 59, pp. 1340–1350, 2007.
View at: Publisher Site | Google Scholar
R. W. Sands and D. J. Mooney, “Polymers to direct cell fate by controlling the microenvironment,” Current Opinion in Biotechnology, vol. 18, pp. 448–453, 2007.
View at: Publisher Site | Google Scholar
A. Friggeri, B. L. Feringa, and J. van Esch, “Entrapment and release of quinoline derivatives using a hydrogel of a low molecular weight gelator,” Journal of Controlled Release, vol. 97, pp. 241–248, 2004.
View at: Publisher Site | Google Scholar
A. Shome, S. Debnath, and P. K. Das, “Head group modulated pH-responsive hydrogel of amino acid-based amphiphiles: entrapment and release of cytochromec and vitamin B12,” Langmuir, vol. 24, pp. 4280–4288, 2008.
View at: Publisher Site | Google Scholar
H. Shen, H. Lin, A. X. Sun et al., “Acceleration of chondrogenic differentiation of human mesenchymal stem cells by sustained growth factor release in 3D graphene oxide incorporated hydrogels,” Acta Biomaterialia, vol. 105, pp. 44–55, 2020.
View at: Publisher Site | Google Scholar
M. Wang, L. Chen, and Z. Zhang, “Potential Applications of Alginate Oligosaccharides for Biomedicine – A Mini Review,” Carbohydrate Polymers, vol. 271, Article ID 118408, 2021.
View at: Publisher Site | Google Scholar
A. Moshaverinia, X. Xu, C. Chen, K. Akiyama, M. L. Snead, and S. Shi, “Dental mesenchymal stem cells encapsulated in an alginate hydrogel co-delivery microencapsulation system for cartilage regeneration,” Acta Biomaterialia, vol. 9, pp. 9343–9350, 2013.
View at: Publisher Site | Google Scholar
P. Gentile, C. Ghione, A. M. Ferreira, A. Crawford, and P. V. Hatton, “Alginate-based hydrogels functionalised at the nanoscale using layer-by-layer assembly for potential cartilage repair,” Biomaterials Science, vol. 5, pp. 1922–1931, 2017.
View at: Publisher Site | Google Scholar
K. S. Masters, “Covalent growth factor immobilization strategies for tissue repair and regeneration,” Macromolecular Bioscience, vol. 11, pp. 1149–1163, 2011.
View at: Publisher Site | Google Scholar
J. D. Mccall, J. E. Luoma, and K. S. Anseth, “Covalently tethered transforming growth factor beta in PEG hydrogels promotes chondrogenic differentiation of encapsulated human mesenchymal stem cells,” Drug Delivery and Translational Research, vol. 2, pp. 305–312, 2012.
View at: Publisher Site | Google Scholar
T. Böck, V. Schill, M. Krähnke et al., “TGF-β1-Modified hyaluronic acid/poly(glycidol) hydrogels for chondrogenic differentiation of human mesenchymal stromal cells,” Macromolecular Bioscience, vol. 18, Article ID 1700390, 2018.
View at: Publisher Site | Google Scholar
S. M. Willerth and S. E. Sakiyama-Elbert, “Approaches to neural tissue engineering using scaffolds for drug delivery,” Advanced Drug Delivery Reviews, vol. 59, no. 4-5, pp. 325–338, 2007.
View at: Publisher Site | Google Scholar
W. J. King and P. H. Krebsbach, “Growth factor delivery: how surface interactions modulate release in vitro and in vivo,” Advanced Drug Delivery Reviews, vol. 64, pp. 1239–1256, 2012.
View at: Publisher Site | Google Scholar
D. R. Griffin, J. L. Schlosser, S. F. Lam, T. H. Nguyen, H. D. Maynard, and A. M. Kasko, “Synthesis of photodegradable macromers for conjugation and release of bioactive molecules,” Biomacromolecules, vol. 14, pp. 1199–1207, 2013.
View at: Publisher Site | Google Scholar
B. Choi, S. Kim, J. Fan et al., “Covalently conjugated transforming growth factor-β1 in modular chitosan hydrogels for the effective treatment of articular cartilage defects,” Biomaterials Science, vol. 3, pp. 742–752, 2015.
View at: Publisher Site | Google Scholar
A. C. Daly, L. Riley, T. Segura, and J. A. Burdick, “Hydrogel microparticles for biomedical applications,” Nature Reviews Materials, vol. 5, pp. 20–43, 2020.
View at: Publisher Site | Google Scholar
W. Leong, T. T. Lau, and D. A. Wang, “A temperature-cured dissolvable gelatin microsphere-based cell carrier for chondrocyte delivery in a hydrogel scaffolding system,” Acta Biomaterialia, vol. 9, pp. 6459–6467, 2013.
View at: Publisher Site | Google Scholar
L. Deveza, J. Ashoken, G. Castaneda et al., “Microfluidic synthesis of biodegradable polyethylene-glycol microspheres for controlled delivery of proteins and DNA nanoparticles,” ACS Biomaterials Science & Engineering, vol. 1, pp. 157–165, 2015.
View at: Publisher Site | Google Scholar
M. E. Helgeson, S. C. Chapin, and P. S. Doyle, “Hydrogel microparticles from lithographic processes: novel materials for fundamental and applied colloid science,” Current Opinion in Colloid & Interface Science, vol. 16, pp. 106–117, 2011.
View at: Publisher Site | Google Scholar
S. M. Naqvi, S. Vedicherla, J. Gansau, T. Mcintyre, M. Doherty, and C. T. Buckley, “Living cell factories - electrosprayed microcapsules and microcarriers for minimally invasive delivery,” Advances in Materials, vol. 28, pp. 5662–5671, 2016.
View at: Publisher Site | Google Scholar
A. Sinclair, M. B. O'Kelly, T. Bai, H. C. Hung, P. Jain, and S. Jiang, “Self healing zwitterionic microgels as a versatile platform for malleable cell constructs and injectable therapies,” Advanced Materials, vol. 30, Article ID 1803087, 2018.
View at: Publisher Site | Google Scholar
T. J. Hinton, Q. Jallerat, R. N. Palchesko et al., “Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels,” Science Advances, vol. 1, no. 9, Article ID e1500758, 2015.
View at: Publisher Site | Google Scholar
M. Ahearne, Y. Liu, and D. J. Kelly, “Combining freshly isolated chondroprogenitor cells from the infrapatellar fat pad with a growth factor delivery hydrogel as a putative single stage therapy for articular cartilage repair,” Tissue Engineering Part A, vol. 20, no. 5-6, pp. 930–939, 2014.
View at: Publisher Site | Google Scholar
R. Reyes, A. Delgado, R. Solis et al., “Cartilage repair by local delivery of transforming growth factor-β1 or bone morphogenetic protein-2 from a novel, segmented polyurethane/polylactic-co-glycolic bilayered scaffold,” Journal of Biomedical Materials Research Part A, vol. 102, pp. 1110–1120, 2014.
View at: Publisher Site | Google Scholar
S. J. Lin, Y. C. Chan, Z. C. Su, W. L. Yeh, P. L. Lai, and I. M. Chu, “Growth factor‐loaded microspheres inmPEG polypeptide hydrogel system for articular cartilage repair,” Journal of Biomedical Materials Research Part A, vol. 109, pp. 2516–2526, 2021.
View at: Publisher Site | Google Scholar
T. A. Holland, Y. Tabata, and A. G. Mikos, “Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering,” Journal of Controlled Release, vol. 101, no. 1-3, pp. 111–125, 2005.
View at: Publisher Site | Google Scholar
A. Jaklenec, A. Hinckfuss, B. Bilgen, D. M. Ciombor, R. Aaron, and E. Mathiowitz, “Sequential release of bioactive IGF-I and TGF-beta 1 from PLGA microsphere-based scaffolds,” Biomaterials, vol. 29, pp. 1518–1525, 2008.
View at: Publisher Site | Google Scholar
F. Han, F. Zhou, X. Yang, J. Zhao, Y. Zhao, and X. Yuan, “A pilot study of conically graded chitosan-gelatin hydrogel/PLGA scaffold with dual-delivery of TGF-β1 and BMP-2 for regeneration of cartilage-bone interface,” Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 103, pp. 1344–1353, 2015.
View at: Publisher Site | Google Scholar
Z. Qiao, M. Lian, Y. Han et al., “Bioinspired Stratified Electrowritten Fiber-Reinforced Hydrogel Constructs with Layer-specific Induction Capacity for Functional Osteochondral Regeneration,” Biomaterials, Article ID 120385, 2021.
View at: Publisher Site | Google Scholar
Y. Zhu, M. Yuan, H. Y. Meng et al., “Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: a review,” Osteoarthritis and Cartilage, vol. 21, pp. 1627–1637, 2013.
View at: Publisher Site | Google Scholar
J. V. D. Dolder, R. Mooren, A. P. Vloon, P. J. Stoelinga, and J. A. Jansen, “Platelet-rich plasma: quantification of growth factor levels and the effect on growth and differentiation of rat bone marrow cells,” Tissue Engineering, vol. 12, pp. 3067–3073, 2006.
View at: Publisher Site | Google Scholar
H. Lu, W. Chang, M. Tsai, C. Chen, W. Chen, and F. Mi, “Development of injectable fucoidan and biological macromolecules hybrid hydrogels for intra-articular delivery of platelet-rich plasma,” Marine Drugs, vol. 17, p. 236, 2019.
View at: Publisher Site | Google Scholar
X. Liu, Y. Yang, X. Niu et al., “An in situ photocrosslinkable platelet rich plasma – complexed hydrogel glue with growth factor controlled release ability to promote cartilage defect repair,” Acta Biomaterialia, vol. 62, pp. 179–187, 2017.
View at: Publisher Site | Google Scholar
D. J. Soomekh, “Current concepts for the use of platelet-rich plasma in the foot and ankle,” Clinics in Podiatric Medicine and Surgery, vol. 28, pp. 155–170, 2011.
View at: Publisher Site | Google Scholar
E. Jooybar, M. J. Abdekhodaie, M. Alvi, A. Mousavi, M. Karperien, and P. J. Dijkstra, “An injectable platelet lysate-hyaluronic acid hydrogel supports cellular activities and induces chondrogenesis of encapsulated mesenchymal stem cells,” Acta Biomaterialia, vol. 83, pp. 233–244, 2019.
View at: Publisher Site | Google Scholar
M. Kim, I. E. Erickson, M. Choudhury, N. Pleshko, and R. L. Mauck, “Transient exposure to TGF-3 improves the functional chondrogenesis of MSC-laden hyaluronic acid hydrogels,” Journal of the Mechanical Behavior of Biomedical Materials, vol. 11, pp. 92–101, 2012.
View at: Publisher Site | Google Scholar
J. N. Zara, R. K. Siu, X. Zhang et al., “High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation in Vivo,” Tissue Engineering Part A, vol. 9, pp. 1389–10, 2011.
View at: Publisher Site | Google Scholar
A. Saraf and A. G. Mikos, “Gene delivery strategies for cartilage tissue engineering,” Advanced Drug Delivery Reviews, vol. 58, pp. 592–603, 2006.
View at: Publisher Site | Google Scholar
R. S. Goomer, T. M. Maris, R. Gelberman, M. Boyer, M. Silva, and D. Amiel, “Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair,” Clinical Orthopaedics and Related Research, vol. 379, no. Suppl, pp. S189–S200, 2000.
View at: Publisher Site | Google Scholar
H. Madry, L. Gao, A. Rey Rico et al., “Thermosensitive hydrogel based on PEO–PPO–PEO poloxamers for a controlled in situ release of recombinant adeno associated viral vectors for effective gene therapy of cartilage defects,” Advanced Materials, vol. 32, Article ID 1906508, 2020.
View at: Publisher Site | Google Scholar
M. W. Grol and B. H. Lee, “Gene therapy for repair and regeneration of bone and cartilage,” Current Opinion in Pharmacology, vol. 40, pp. 59–66, 2018.
View at: Publisher Site | Google Scholar
S. Raisin, E. Belamie, and M. Morille, “Non-viral Gene Activated Matrices for Mesenchymal Stem Cells Based Tissue Engineering of Bone and Cartilage,” Biomaterials, vol. 104, pp. 223–37, 2016.
View at: Publisher Site | Google Scholar
M. Cucchiarini and H. Madry, “Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair,” Nature Reviews Rheumatology, vol. 15, pp. 18–29, 2019.
View at: Publisher Site | Google Scholar
J. Maihöfer, H. Madry, A. Rey Rico et al., “Hydrogel Guided, rAAV mediated IGF I overexpression enables long‐term cartilage repair and protection against perifocal osteoarthritis in a large animal full thickness chondral defect model at one year in vivo,” Advanced Materials (Weinheim, Germany), vol. 33, Article ID e2008451, 2021.
View at: Publisher Site | Google Scholar
M. Weißenberger, M. H. Weißenberger, M. Wagenbrenner et al., “Different types of cartilage neotissue fabricated from collagen hydrogels and mesenchymal stromal cells via SOX9, TGFB1 or BMP2 gene transfer,” PLoS One, vol. 15, Article ID e0237479, 2020.
View at: Publisher Site | Google Scholar
M. Morille, C. Passirani, A. Vonarbourg, A. Clavreul, and J. P. Benoit, “Progress in Developing Cationic Vectors for Non-viral Systemic Gene Therapy against Cancer,” Biomaterials, vol. 24, pp. 3477–25, 2008.
View at: Publisher Site | Google Scholar
L. S. Costard, D. C. Kelly, R. N. Power et al., “Layered double hydroxide as a potent non-viral vector for nucleic acid delivery using gene-activated scaffolds for tissue regeneration applications,” Pharmaceutics, vol. 12, p. 1219, 2020.
View at: Publisher Site | Google Scholar
H. Madry, G. Kaul, M. Cucchiarini et al., “Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I),” Gene Therapy, vol. 12, pp. 1171–1179, 2005.
View at: Publisher Site | Google Scholar
H. Lu, L. Lv, Y. Dai, G. Wu, H. Zhao, and F. Zhang, “Porous chitosan scaffolds with embedded hyaluronic acid/chitosan/plasmid-DNA nanoparticles encoding TGF-β1 induce DNA controlled release, transfected chondrocytes, and promoted cell proliferation,” PLoS One, vol. 8, Article ID e69950, 2013.
View at: Publisher Site | Google Scholar
T. Gonzalez-Fernandez, E. G. Tierney, G. M. Cunniffe, F. J. O'Brien, and D. J. Kelly, “Gene delivery of TGF-β3 and BMP2 in an MSC-laden alginate hydrogel for articular cartilage and endochondral bone tissue engineering,” Tissue Engineering Part A, vol. 22, no. 9-10, pp. 776–787, 2016.
View at: Publisher Site | Google Scholar
A. Khademhosseini, R. Langer, J. Borenstein, and J. P. Vacanti, “Microscale technologies for tissue engineering and biology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, pp. 2480–2487, 2006.
View at: Publisher Site | Google Scholar
J. Chen, H. Chen, P. Li et al., “Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds,” Biomaterials, vol. 32, pp. 4793–4805, 2011.
View at: Publisher Site | Google Scholar

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Copyright © 2022 Jingyan Guan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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