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A Novel Poly(amido amine)-Dendrimer-Based Hydrogel as a Mimic for the Extracellular Matrix Yao Wang, Qiang Zhao, He Zhang, Sheng Yang,* and Xinru Jia* Artificial materials that mimic the extracellular matrix (ECM) of mammalian tissues are clinically needed, but their production remains a challenge.[1] Natural macromolecules—such as collagen,[2] alginate,[3] fibrin,[4] and chitosan[5]—have been used in tissue engineering strategies. These polymers, however, have limited clinical applicability; for example, they may have insufficient mechanical properties, and in the case of collagenbased gels and fibrin matrices, there is inappropriate shrinkage and rapid degradation.[6] In addition, it is difficult to precisely control and modify their macro-structures and to synthesize them at a large scale. In hopes of meeting clinical demands, the development of polymer-based scaffolds containing adhesive peptide ligands as cell recognition sites has attracted much attention. The properties of synthetic polymers can be tailored to match tissue growth in the artificial ECM, and cell recognition sites within the polymers provide biological activity to mimic the physiological environment.[7] There has been increasing interest in hydrogels as scaffolds for cell encapsulation[8] because the high water content in hydrogels may facilitate the diffusion of nutrients and oxygen to the cells and the removal of waste products and carbon dioxide from the cells.[9] In addition, gels with 3D networks create an environment that simulates the native state of cells.[10] A typical example is the hydrogel derived from poly(lactide)b-poly(ethylene glycol)-b-poly(lactide) co-polymers, which has adjustable degradation properties and favorable biocompatibility.[11] However, the limitations of such polymers include excessive volumetric swelling after cross-linking, inferior mechanical properties, and the absence of bioactivity. Hydrogels derived from dendrimers with their unique structures offer an alternative to linear polymers. Dendritic architectures[12]—the most pervasive topologies in biological systems at various dimensional scales—are optimal molecular-level

Y. Wang, Q. Zhao, Prof. X.-R. Jia Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of the Ministry of Education College of Chemistry and Molecular Engineering Peking University Beijing, China Fax: +86-010-62751708 E-mail: [email protected] H. Zhang, Dr. S. Yang Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences College of Stomatology Chongqing Medical University Chongqing, China Fax: +86-023-88860085 E-mail: [email protected]

DOI: 10.1002/adma.201400323

Adv. Mater. 2014, DOI: 10.1002/adma.201400323

nanostructures for creating bio-related materials. This is due to the easily modified surface groups, which not only provide multiple cross-linkingsites but also provide the possibility of conjugating various bioactive components. The in situ photo-cross-linking ability is a highly desirable property for hydrogels used in tissue engineering, especially for trauma repair.[13] Advantages of photo-initiative hydrogels[14] include the possibility of controlling both the spatial and temporal aspects of cross-linking, the ability to conduct crosslinking at physiological temperature and pH, and the ability to fill irregularly shaped defect sites. In-situ cross-linking the hydrogel can also provide better adhesion and mechanical integrity to the defect sites. Herein, we report a novel hydrogel constructed from two components: a linear co-polymer of poly(lactic acid)-bpoly(ethylene glycol)-b-poly(lactic acid) with acrylate end-groups (PEG-LA-DA), and a fourth-generation poly(amido amine) dendrimer (G4.0 PAMAM) peripherally modified by polyethylene glycol (PEG) with terminal arginine–glycine–(aspartic acid)– (D-tyrosine)–cysteine (RGDyC) and acryloyl groups. We have combined the superior properties of PAMAM dendrimers, PEG-LA-DA co-polymers, and in-situ photo-cross-linking to create a hydrogel with a highly interconnected porous 3D network structure. Our hydrogel scaffold offers several advantages over other systems because 1) the multiple cross-linking sites present on the dendrimers can increase the cross-linking density at lower concentrations; 2) the spherical dendrimers may provide discrete ‘molecular islands’ in the network to limit swelling and improve mechanical properties; and 3) the multiple end-groups on the dendrimers facilitate the introduction of functional groups into the system at the nanoscale level. To the best of our knowledge, this is a rare report of a PAMAMdendrimer-based hydrogel with a highly porous structure, which exhibits reduced swelling, enhanced mechanical stiffness, and better cell adhesion, differentiation, and proliferation than hydrogels formed from PEG-LA-DA alone. As shown in Scheme 1, the hydrogel network was fabricated via a photo-induced cross-linking reaction using the modified sphere-like PAMAM dendrimers as the ‘molecular islands’ and the linear co-polymer of PEG-LA-DA as the linkage moiety. PEGLA-DA comprises a PEG chain (molecular weight: 6000 Da) with an average of five repeat units of lactic acid grafted at each side (see the Supporting Information (SI): Figure S1, S2, and S3 and Table S1). Initially, we modified the periphery of the G4.0 PAMAM dendrimers with methoxy-PEG-succinimidyl carbonate ester (mPEG1000-NHS) and maleimide-PEG-succinimidyl carbonate ester (MAL-PEG5000-NHS), in order to make them amenable to derivatization with bioactive components and crosslinking groups and to enhance the biocompatibility and dissolution properties of the dendrimers. The RGDyC and acryloyl

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The acryloyl groups on the exterior of the G4.0 PAMAM dendrimers are also necessary for gelation. Gels were not observed as a result of mixing the control samples of G4.0 PAMAM or GPR with the PEG-LA-DA co-polymers at ratios of 1/10 and 1/5, respectively. 3) It was established that transparent and robust gels can be obtained with AGPR concentrations in the range of 2%–20% with PEG-LA-DA (Figure 1a,b); otherwise, softer gels were observed. SEM was used to visualize the networks Scheme 1. Schematic description of the hydrogel from AGPR and PEG-LA-DA. PLA refers to of the hydrogel. The gel from PEG-LA-DA/ AGPR (at a ratio of 5/1) possessed a highly poly(lactic acid) units. porous structure. As shown, the morphology consisted of pores in the range of 20–50 µm containing sevgroups were then covalently conjugated to the MAL-PEG5000eral smaller holes inside (≈5 µm) (Figure 1c–e; SI: Figure S9). NHS through an effective Michael addition reaction to obtain Hydrogels with differently sized pores are useful in tissue engithe final modified dendrimers, named acryloyl-G4.0-PEGneering because pores with a minimum size of 100 µm are benRGDyC (AGPR) (see SI: Scheme S1). G4.0-PEG-RGDyC (GPR) eficial for tissue growth and vascularization in bone-grafting, (without acryloyl groups) and acryloyl-G4.0-PEG (AGP) (without while pores in the nanometer range can enhance cell adhesion RGDyC groups) were prepared as controls for comparison. 1 and proliferation at the implant site and can potentially absorb H NMR measurements were performed to determine proteins and growth factors.[16] the grafting ratio of PEG, RGDyC, and acryloyl groups (SI: Figure S4) on the exterior of the PAMAM dendrimers. The swelling properties of the hydrogel were examined by According to the integration ratio of the tyrosine protons from immersing the freshly cross-linked hydrogel in PBS at 37 °C RGDyC at 7.02 and 6.72 ppm, the acryloyl protons at 5.76 and for 48 h. AGPR was found to play a key role in controlling 5.10 ppm, the PEG protons at 3.60 ppm, and the PAMAM denthe swelling ratio. Adding 2% AGPR to the system effectively drimer protons at 3.05–2.10 ppm, there are about 10 RGDyC decreased the swelling ratio to 300% (Figure 2), as compared groups, 10 double bonds, and 40 mPEG1000 moieties grafted to a swelling ratio of 1000% for the hydrogel consisting of only onto the periphery of the G4.0 PAMAM dendrimers. The dislinear PEG-LA-DA. The swelling ratio was further reduced to appearance of the peak at 6.76 ppm indicated that most of 180% when AGPR was increased to 20%. The results suggest the maleimide groups of the MAL-PEG5000-NHS chain ends that the reduction in swelling observed in the PEG-LA-DA/ reacted with RGDyC and allyl mercaptan. Differential scanning AGPR hydrogel is a consequence of the “dendritic effect”. The calorimetry (DSC) and Fourier-transform (FT)-IR measuresphere-like PAMAM molecules function as discrete multivalent ments were also performed, and their results supported the 1H junction points that limit the expansion of the networks, leading to less swelling. Restricted expansion of the hydrogel is highly NMR data (SI: Figure S5, S6). desirable for clinical applications to ensure that the gel does not The gelation properties were examined by mixing 20% exceed the trauma boundaries and detach from the wound site. w/v aqueous solution of PEG-LA-DA with different amounts of AGPR (PEG-LA-DA:AGPR = 10/1, 5/1, 2/1, 1/1, or 1/2) in The degradation time of the PEG-LA-DA/AGPR hydrogels phosphate buffered saline (PBS) followed by UV irradiation at at a PEG-LA-DA:AGPR ratio of 10/1, 5/1, 2/1, and 1/1 was 365 nm for 10 min (SI: Table S2). This resulted in three conmeasured to be 30, 36, 39, and 45 days, respectively, indicating clusions: 1) The PEG-LA-DA co-polymer is essential for gelaa controllable manner of degradation. In comparison, the gel tion. Although the sphere-like AGPR contained cross-linking composed only of PEG-LA-DA co-polymer degraded in 27 days groups in the structure, no gelation occurred as a result of the (SI: Figure S10). possible intramolecular and/or intermolecular cross-linking The storage modulus G′ and loss modulus G′′ were measured of the acryloyl units on the exterior of the dendrimers (SI: to assess the mechanical stiffness of the samples (Figure 3a,b; Figure S7). As shown by scanning electron microscopy (SEM) images, the morphology of AGPR (20% w/v solution, after irradiation) was totally different from that of the hydrogel (SI: Figure S8). This result is consistent with that reported for a clay/polymer hydrogel by Aida and co-workers,[15] who found that the mechanical modulus of hydrogels could be enhanced by using long-chain polymers because they can more easily bridge different clay sheets. In contrast, short-chain polymers Figure 1. a,b) Photographs of the hydrogel at room temperature. c–e) SEM images of the lead to cross-linking within the same sheet, hydrogel with scale bars of 500 (c), 100 (d), and 20 (e) µm. The hydrogel was prepared from which reduces the mechanical modulus. 2) PEG-LA-DA/AGPR (at a 5/1 ratio) and fully swelled at 37 °C for 48 h. 2

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indicating that the incorporation of bioactive components, such as RGDyC, did not negatively influence mechanical strength. This result is consistent with the report of Levental and co-workers, who found that the mechanical stiffness of hydrogels was maintained despite the introduction of various peptides.[19] To evaluate the ability of the hydrogel to mimic ECM cues that support stem-cell proliferation and differentiation, we encapsulated mouse bone marrow mesenchymal stem cells Figure 2. a) Equilibrium swelling ratio for PEG-LA-DA alone and PEG-LA-DA/AGPR at ratios of (mMSCs) within the hydrogel. Hydrogels at 10/1, 5/1, 2/1, and 1/1, measured on the indicated days. b) The average swelling ratio for PEG- a 5/1 ratio for both PEG-LA-DA/AGPR and LA-DA alone and PEG-LA-DA/AGPR at ratios of 10/1, 5/1, 2/1, and 1/1 (n, number of tests > 3). PEG-LA-DA/AGP were evaluated, and PEGThe hydrogels were immersed in PBS buffer at 37 °C for 48 h, and then dried for degradation LA-DA alone was used as the control. For the testing; the whole process was sustained for over 50 days. hyrdogel of PEG-LA-DA/AGPR, evidence of cell toxicity was not observed within the 7 days SI: Table S3) as a function of the angular frequency at a fixed that the cells were incubated in the hydrogel (SI: Figure S12); it strain, γ = 10%. The G′ values of the samples were larger than showed more cell viability than the control sample. In contrast, that of G′′ over the range of frequencies tested (from 0.1 to hydrogels without RGDyC (PEG-LA-DA/AGP) had reduced cell 100 rad s−1), and all samples showed a single plateau region viability, suggesting that introducing RGDyC into the hydrogel in the dynamic moduli. Notably, the mechanical stiffness of increased cell attachment and proliferation. the hydrogels was obviously enhanced by adding AGPR to the H&E staining indicated that the cells were evenly distributed system; particular enhancement was attained when the AGPR in the hydrogel pores (Figure 4a). The 3D culture within the content reached 4%. This is due to 1) the increase in crosshydrogel enabled the cells to maintain their natural morphology linking density, resulting from multiple cross-linking sites on while communicating with the surrounding microenvironment the periphery of the PAMAM dendrimers; and 2) the amide and responding to each other within an in vitro model system. structures of PAMAM, which may allow for better gel stiffDAPI–actin staining (DAPI = 4′,6′-diamino-2-phenylindole) ness than gels containing ester bonds.[17] However, intra- and/ showed that the cells in the hydrogel with coupled RGDyC or intermolecular cross-linking reactions may occur among the exhibited stronger stress fibers than those in the control sample AGPR themselves (SI: Figure S7) at higher concentration ratios (PEG-LA-DA alone); this may be due to enhanced cell adhesion (PEG-LA-DA:AGPR = 2/1, 1/1, 1/2), thus leading to a looser and differentiation supported by the framework (Figure 4a).[20] network, and consequently lower elastic moduli. Strain amplitude sweeps demonstrated a broad elastic It has been reported that the RGDyC presence can trigger response range (Figure 3c). The G′ and G′′ values were constant α5β1 integrin receptor activation in mMSCs, which further until the strain increased to 1000% (yielding point), indicating promotes osteoblast proliferation and leads to an increased that the hydrogel could withstand a wide range of deformabone regeneration capacity.[21] Real-time polymerase chain tion. This is a desirable property for bone repair or tissue engireaction (PCR) analysis showed that the mRNA level of alkaneering applications because the gel would need to withstand line phosphatase (ALP), an early osteogenic marker of mMSC environmental changes resulting from mechanical loading. differentiation, was significantly increased in cells cultured in We assume that the PEG-LA-DA co-polymers act as soft ductile the PEG-LA-DA/AGPR hydrogel as compared to the hydrogel components to dissipate the stress, while the dendrimers are without RGDyC (Figure 4b). Expression of the bone differenthe hard units that enhance the modulus of the network.[18] tiation markers osterix (OSX), parathyroid hormone 1 receptor (PTH1R), and osteocalcin (OC) was also significantly up-reguIn order to better understand the properties of the hydrogel, lated. The results suggest that the novel PAMAM-dendrimerwe also evaluated the modulus of samples prepared by mixing based hydrogel provides chemical and physical cues supporting 4% AGPR or 4% AGP with 20% PEG-LA-DA (SI: Figure S11). mMSC osteogenic differentiation. A similar storage modulus was observed for the two gels,

Figure 3. Plots of the angular frequency (ω) versus a) storage modulus (G′) and b) loss modulus (G′′) of the hydrogels at different PEG-LA-DA:AGPR ratios (1/0 (PEG-LA-DA alone), 10/1, 5/1, 2/1, 1/1, 1/2). c) Oscillatory rheological measurements for PEG-LA-DA/AGPR at a 5/1 ratio.

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Figure 4. a) H&E staining and DAPI–actin staining of MSCs in the hydrogel 3 days after encapsulation. Control: PEG-LA-DA (Linear); Test: PEG-LADA/AGPR = 5/1. b) Real-time PCR analysis for mMSC osteogenic differentiation. Alkaline phosphatase (ALP), osterix (OSX), parathyroid hormone 1 receptor (PTH1R), and osteocalcin (OC) were evaluated by real-time PCR to assess differentiation in the hydrogels at 4 and 7 days. 18S was used as a housekeeping gene. Control: PEG-LA-DA:AGP = 5/1; Test: PEG-LA-DA:AGPR = 5/1.

In conclusion, we have constructed a novel hydrogel system that mimics the ECM of native tissues. The introduction of AGPR in the gel promotes a highly porous network and effectively improves hydrogel properties, including an increase in mechanical stiffness and a reduction in the swelling ratio. The PAMAM-dendrimer-based hydrogel supported mMSC proliferation and differentiation in the absence of cytotoxic effects. This dendrimer-based hydrogel may serve as a model for developing advanced materials with novel properties for applications in tissue engineering.

Experimental Section The synthetic procedures and characterization of AGPR and PEG-LA-DA, as well as the preparation and properties of the hydrogels, are described in detail in the SI. The 1H NMR and FT-IR spectra, the GPC trails, SEM images, degradation profiles, and the cell viability assay are also provided in the SI.

Supporting Information Supporting Information is available from the Wiley Online Library or from the author.

Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21174005 and 21274004) through X.R.J. and the Chongqing Science and Technology Commission Natural Science Foundation of China (cstc2012jjA0178) through S.Y. Received: January 21, 2014 Revised: February 26, 2014 Published online:

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A novel poly(amido amine)-dendrimer-based hydrogel as a mimic for the extracellular matrix.

The extracellular matrix is mimicked by a novel dendrimer-based hydrogel, which exhibits a highly interconnected porous network, enhanced mechanical s...
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