Intradiscal application of a PCLA–PEG–PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What's in it for humans?

Chronic low back pain is a common clinical problem in both the human and canine population. Current pharmaceutical treatment often consists of oral anti‐inflammatory drugs to alleviate pain. Novel treatments for degenerative disc disease focus on local application of sustained released drug formulations. The aim of this study was to determine safety and feasibility of intradiscal application of a poly(ε‐caprolactone‐co‐lactide)‐b‐poly(ethylene glycol)‐bpoly(ε‐caprolactone‐co‐lactide) PCLA–PEG–PCLA hydrogel releasing celecoxib, a COX‐2 inhibitor. Biocompatibility was evaluated after subcutaneous injection in mice, and safety of intradiscal injection of the hydrogel was evaluated in experimental dogs with early spontaneous intervertebral disc (IVD) degeneration. COX‐2 expression was increased in IVD samples surgically obtained from canine patients, indicating a role of COX‐2 in clinical IVD disease. Ten client‐owned dogs with chronic low back pain related to IVD degeneration received an intradiscal injection with the celecoxib‐loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. The hydrogel did not influence magnetic resonance imaging signal at long‐term follow‐up. Clinical improvement was achieved by reduction of back pain in 9 of 10 dogs, as was shown by clinical examination and owner questionnaires. In 3 of 10 dogs, back pain recurred after 3 months. This study showed the safety and effectiveness of intradiscal injections in vivo with a thermoresponsive PCLA–PEG–PCLA hydrogel loaded with celecoxib. In this set‐up, the dog can be used as a model for the development of novel treatment modalities in both canine and human patients with chronic low back pain.     

Calcium deposition in photocrosslinked poly(Pro‐Hyp‐Gly) hydrogels encapsulated rat bone marrow stromal cells

Reproducing the features of the extracellular matrix is important for fabricating three‐dimensional (3D) scaffolds for tissue regeneration. A collagen‐like polypeptide, poly(Pro‐Hyp‐Gly), is a promising material for 3D scaffolds because of its excellent physical properties, biocompatibility, and biodegradability. In this paper, we present a novel photocrosslinked poly(Pro‐Hyp‐Gly) hydrogel as a 3D scaffold for simultaneous rat bone marrow stromal cell (rBMSC) encapsulation. The hydrogels were fabricated using visible‐light photocrosslinking at various concentrations of methacrylated poly(Pro‐Hyp‐Gly) (20–50 mg/ml) and irradiation times (3 or 5 min). The results show that the rBMSCs encapsulated in the hydrogels survived 7 days of incubation. Calcium deposition on the encapsulated rBMSCs was assessed with scanning electron microscope observation, Alizarin Red S, and von Kossa staining. The most strongly stained area was observed in the hydrogel formed with 30 mg/ml of methacrylated poly(Pro‐Hyp‐Gly) with 5‐min irradiation. These findings demonstrate that poly(Pro‐Hyp‐Gly) hydrogels support rBMSC viability and differentiation, as well as demonstrating the feasibility of using poly(Pro‐Hyp‐Gly) hydrogels as a cytocompatible, biodegradable 3D scaffold for tissue regeneration.     

Visualizing cell‐laden fibrin‐based hydrogels using cryogenic scanning electron microscopy and confocal microscopy

The present investigation explores the microscopic aspects of cell‐laden hydrogels at high resolutions, using three‐dimensional cell cultures in semi‐synthetic constructs that are of very high water content (>98% water). The study aims to provide an imaging strategy for these constructs, while minimizing artefacts. Constructs of poly(ethylene glycol)‐fibrinogen and fibrin hydrogels containing embedded mesenchymal cells (human dermal fibroblasts) were first imaged by confocal microscopy. Next, high‐resolution scanning electron microscopy (HR‐SEM) was used to provide images of the cells within the hydrogels, at submicron resolutions. Because it was not possible to obtain artefact‐free images of the hydrogels using room‐temperature HR‐SEM, a cryogenic HR‐SEM imaging methodology was employed to visualize the sample while preserving the natural hydrated state of the hydrogel. The ultrastructural details of the constructs were observed at subcellular resolutions, revealing numerous cellular components, the biomaterial in its native configuration, and the uninterrupted cell membrane as it relates with the biomaterial in the hydrated state of the construct. Constructs containing microscopic albumin microbubbles were also imaged using these methodologies to reveal fine details of the interaction between the cells, the microbubbles, and the hydrogel. Taken together with the confocal microscopy, this imaging strategy provides a more complete picture of the hydrated state of the hydrogel network with cells inside. As such, this methodology addresses some of the challenges of obtaining this information in amorphous hydrogel systems containing a very high water content (>98%) with embedded cells. Such insight may lead to better hydrogel‐based strategies for tissue engineering and regeneration.     

Characterization of novel akermanite:poly‐ϵ‐caprolactone scaffolds for human adipose‐derived stem cells bone tissue engineering

In this study, three different akermanite:poly‐?‐caprolactone (PCL) composite scaffolds (wt%: 75:25, 50:50, 25:75) were characterized in terms of structure, compression strength, degradation rate and in vitro biocompatibility to human adipose‐derived stem cells (hASC). Pure ceramic scaffolds [CellCeram^TM, custom‐made, 40:60 wt%; β‐tricalcium phosphate (β‐TCP):hydroxyapatite (HA); and akermanite] and PCL scaffolds served as experimental controls. Compared to ceramic scaffolds, the authors hypothesized that optimal akermanite:PCL composites would have improved compression strength and comparable biocompatibility to hASC. Electron microscopy analysis revealed that PCL‐containing scaffolds had the highest porosity but CellCeram^TM had the greatest pore size. In general, compression strength in PCL‐containing scaffolds was greater than in ceramic scaffolds. PCL‐containing scaffolds were also more stable in culture than ceramic scaffolds. Nonetheless, mass losses after 21 days were observed in all scaffold types. Reduced hASC metabolic activity and increased cell detachment were observed after acute exposure to akermanite:PCL extracts (wt%: 75:25, 50:50). Among the PCL‐containing scaffolds, hASC cultured for 21 days on akermanite:PCL (wt%: 75:25) discs displayed the highest viability, increased expression of osteogenic markers (alkaline phosphatase and osteocalcin) and lowest IL‐6 expression. Together, the results indicate that akermanite:PCL composites may have appropriate mechanical and biocompatibility properties for use as bone tissue scaffolds. Copyright © 2012 John Wiley & Sons, Ltd.     

In vitro and in vivo co‐culture of chondrocytes and bone marrow stem cells in photocrosslinked PCL–PEG–PCL hydrogels enhances cartilage formation

Chondrocytes (CH) and bone marrow stem cells (BMSCs) are sources that can be used in cartilage tissue engineering. Co‐culture of CHs and BMSCs is a promising strategy for promoting chondrogenic differentiation. In this study, articular CHs and BMSCs were encapsulated in PCL–PEG–PCL photocrosslinked hydrogels for 4 weeks. Various ratios of CH:BMSC co‐cultures were investigated to identify the optimal ratio for cartilage formation. The results thus obtained revealed that co‐culturing CHs and BMSCs in hydrogels provides an appropriate in vitro microenvironment for chondrogenic differentiation and cartilage matrix production. Co‐culture with a 1:4 CH:BMSC ratio significantly increased the synthesis of GAGs and collagen. In vivo cartilage regeneration was evaluated using a co‐culture system in rabbit models. The co‐culture system exhibited a hyaline chondrocyte phenotype with excellent regeneration, resembling the morphology of native cartilage. This finding suggests that the co‐culture of these two cell types promotes cartilage regeneration and that the system, including the hydrogel scaffold, has potential in cartilage tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.     

Surface modification of poly(ε‐caprolactone) porous scaffolds using gelatin hydrogel as the tracheal replacement

This study evaluates the feasibility of poly(ε‐caprolactone) as a tracheal replacement. To improve biocompatibility, the lumen was modified by gelatin hydrogel crosslinked with two different reagents, EDC and genipin. It was found that the choice of crosslinking agents could significantly affect human lung carcinoma cell proliferation. Genipin‐crosslinked gelatin hydrogel had significantly better cell proliferation than EDC‐crosslinked hydrogel. The study further investigated the performance of the PCL tube modified by genipin‐crosslinked gelatin, using a rabbit tracheal implantation model with implants harvested and histologically examined. In vivo results showed that the PCL tube possessed suitable mechanical properties for resisting collapse during implantation. Additionally, PCL modified by genipin‐crosslinked gelatin was found to suppress granulation tissue growth and prolong animal survival time in comparison with the original PCL tube. Genipin could be an effective treatment to reduce granulation tissue formation at the tracheal anastomoses. Copyright © 2010 John Wiley & Sons, Ltd.     

PDLA/PLLA and PDLA/PCL nanofibers with a chitosan‐based hydrogel in composite scaffolds for tissue engineered cartilage

Osteoarthritis (OA) is the most prevalent musculoskeletal disease in humans, causing pain, loss of joint motility and function, and severely reducing the standard of living of patients. Cartilage tissue engineering attempts to repair the damaged tissue of individuals suffering from OA by providing mechanical support to the joint as new tissue regenerates. The aim of this study was to create composite three dimensional scaffolds comprised of electrospun poly(D,L‐lactide)/poly(L‐lactide) (PDLA/PLLA) or poly(D,L‐lactide)/polycaprolactone (PDLA/PCL) with salt leached pores and an embedded chitosan hydrogel to determine the potential of these scaffolds for cartilage tissue engineering. PDLA/PLLA‐hydrogel scaffolds displayed the largest compressive moduli followed by PDLA/PCL‐hydrogel scaffolds. Dynamic mechanical tests showed that the PDLA/PLLA scaffolds had no appreciable recovery while PDLA/PCL scaffolds did exhibit some recovery. Primary canine chondrocytes produced both collagen type II and proteoglycans (primary components of extracellular matrix in cartilage) while being cultured on scaffolds composed of electrospun PDLA/PCL. As a result, a composite electrospun embedded hydrogel scaffold shows promise for treating individuals suffering from OA. Copyright © 2012 John Wiley & Sons, Ltd.     

Controlled degradation of low-fouling poly(oligo(ethylene glycol)methyl ether methacrylate) hydrogels

Degradable low-fouling hydrogels are ideal vehicles for drug and cell delivery. For each application, hydrogel degradation rate must be re-optimized for maximum therapeutic benefit. We developed a method to rapidly and predictably tune degradation rates of low-fouling poly(oligo(ethylene glycol)methyl ether methacrylate) (P(EG)_xMA) hydrogels by modifying two interdependent variables: (1) base-catalysed crosslink degradation kinetics, dependent on crosslinker electronics (electron withdrawing groups (EWGs)); and, (2) polymer hydration, dependent on the molecular weight (M_W) of poly(ethylene glycol) (PEG) pendant groups. By controlling PEG M_W and EWG strength, P(EG)_xMA hydrogels were tuned to degrade over 6 to 52 d. A 6-member P(EG)_xMA copolymer library yielded slow and fast degrading low-fouling hydrogels suitable for short- and long-term delivery applications. The degradation mechanism was also applied to RGD-functionalized poly(carboxybetaine methacrylamide) (PCBMAA) hydrogels to achieve slow (∼50 d) and fast (∼13 d) degrading low-fouling, bioactive hydrogels.

To tune degradation rates of low-fouling hydrogels, a 6-member P(EG)_xMA copolymer library with different electronics and hydration levels was developed.     

In situ forming degradable networks and their application in tissue engineering and drug delivery.

Multifunctional macromers based on poly(ethylene glycol) and poly(vinyl alcohol) were photopolymerized to form degradable hydrogel networks. The degradation behavior of the highly swollen gels was characterized by monitoring changes in their mass loss, degree of swelling, and compressive modulus. Experimental results show that the modulus decreases exponentially with time, while the volumetric swelling ratio increases exponentially. A degradation mechanism assuming pseudo first-order hydrolysis kinetics and accounting for the structure of the crosslinked networks successfully predicted the experimentally observed trends in these properties with degradation. Once verified, the proposed degradation mechanism was extended to correlate network degradation kinetics, and subsequent changes in network structure, with release behavior of bioactive molecules from these dynamic systems. A theoretical model utilizing a statistical approach to predict the cleavage of crosslinks within the network was used to predict the complex erosion profiles produced by these hydrogels. Finally, the application of these macromers as in situ forming hydrogel constructs for cartilage tissue engineering is demonstrated.     

Culture of preantral follicles in poly(ethylene) glycol‐based,three‐dimensional hydrogel: a relationship between swelling ratio and follicular developments

This study was undertaken to examine how the softness of poly(ethylene) glycol (PEG)‐based hydrogels, creating a three‐dimensional (3D) microenvironment, influences the in vitro growth of mouse ovarian follicles. Early secondary, preantral follicles of 2 week‐old mice were cultured in a crosslinked four‐arm PEG hydrogel. The hydrogel swelling ratio, which relates to softness, was modified within the range 25.7–15.5 by increasing the reactive PEG concentration in the precursor solution from 5% to 15% w/v, but it did not influence follicular growth to form the pseudoantrum (60–80%; p = 0.76). Significant (p < 0.04) model effects, however, were detected in the maturation and developmental competence of the follicle‐derived oocytes. A swelling ratio of > 21.4 yielded better oocyte maturation than other levels, while the highest competence to develop pronuclear and blastocyst formation was detected at 20.6. In conclusion, gel softness, as reflected in swelling ratio, was one of the essential factors for supporting folliculogenesis in vivo within a hydrogel‐based, 3D microenvironment. © 2014 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.     

Temperature-responsive and degradable hyaluronic acid/Pluronic composite hydrogels for controlled release of human growth hormone

Temperature-sensitive hyaluronic acid (HA) hydrogels were synthesized by photopolymerization of vinyl group modified HA in combination with acrylate group end-capped poly(ethylene glycol)–poly(propylene glycol)–poly(ethylene glycol) tri-block copolymer (Pluronic F127). The synthesized HA/Pluronic composite hydrogels gradually collapsed with increasing temperature over the range of 5–40 °C, suggesting that the Pluronic component formed self-associating micelles in the hydrogel structure. Upon prolonged incubation in a buffer medium, the micelles slowly degraded due to the hydrolytic scission of the ester linkage between the Pluronic and acrylate group. The mass erosion occurred much faster at 37 °C than at 13 °C, indicating that at the higher temperature, the ester linkage between the Pluronic and acrylate group might be more exposed to an aqueous environment and thus be more readily hydrolyzed due to Pluronic micellization. Incorporation of recombinant human growth hormone in the hydrogel resulted in a sustained release profile which followed a mass erosion pattern.     

Non-viral vector delivery from PEG-hyaluronic acid hydrogels

Hydrogels have been widely used in tissue engineering as a support for tissue formation or to deliver non-viral gene therapy vectors locally. Hydrogels that combine these functionalities can provide a fundamental tool to promote specific cellular processes leading to tissue formation. This report investigates controlled release of gene therapy vectors from hydrogels as a function of the physical properties for both the hydrogel and the vector. Hydrogels were formed by photocrosslinking acryl-modified hyaluronic acid (HA) with a 4-arm poly(ethylene glycol) (PEG) acryl. The polymer content, and relative composition of HA and PEG modulated the swelling ratio, water content, and degradation, which can influence transport of the vector through the hydrogel. All hydrogels had a water content of 94% or higher, though the water content and swelling ratio increased with a decrease in the PEG:HA ratio. Plasmids were stably incorporated into the hydrogel, with a majority of the release occurring during the initial 2 days. For incubation in buffer, the cumulative release increased with a decreasing PEG or increasing HA content, with approximately 20% to 80% released during the first week depending on the hydrogel composition. Hydrogels incubated in hyaluronidase, an enzyme that degrades HA, significantly increased plasmid release for hydrogels containing 4% PEG and 4% HA-Acryl. The encapsulation of plasmid complexed with polyethylenimine had less than 14% of the complexes released from the hydrogel both in the presence and absence of hyaluronidase. The limited release of the complexes likely results from the complex size and interactions between the vector and hydrogel. These studies demonstrate the dependence of non-viral vector release on the physical properties of the hydrogel and the vector, suggesting vector and hydrogel designs for maximizing localized delivery of non-viral vectors.     

Poly(ethylene carbonate)s, part II: degradation mechanisms and parenteral delivery of bioactive agents.

The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2-*, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC is biodegraded by surface erosion without significant change in the molecular weight of the residual polymer mass. The non-hydrolytic biodegradation by cells producing O2-* is unique among the polymers used as biodegradable drug carriers. The main degradation product of PEC in aqueous systems is ethylene glycol, formed presumably by hydrolysis of ethylene carbonate. The splitting off of a five-membered ring structure from the polymer chain indicates a chain reaction mechanism for the biodegradation. PEC is a suitable drug carrier, particularly for labile drugs. Using human interleukin-3 and octreotide as model drugs, surface erosion of the PEC formulations was indicated by a 1:1 correlation between drug release and polymer mass loss.     

In vivo biocompatibility and biodegradation of poly(ethylene carbonate).

Biodegradation and biocompatibility of poly(ethylene carbonate) (PEC) was examined using an in vivo cage implant system. Exudate analysis showed that PEC and PEC degradation products were biocompatible and induced minimal inflammatory and wound healing responses. Adherent foreign body giant cells (FBGCs) caused pitting on the PEC surface, which led to extensive degradation over time. Data obtained from molecular weight and examination of film cross-sections in the scanning electron microscope (SEM) indicated that PEC underwent surface erosion with no change to the remaining bulk. Attenuated total reflectance infrared (ATR-FTIR) spectroscopy was used to characterize the chemical degradation. Superoxide anion released from inflammatory cells appeared to initiate an "unzipping" mechanism of degradation by deprotonation of PEC hydroxyl end groups. The resulting alkoxide ion participated in a concerted mechanism involving water and the carbonate carbonyl, leading to elimination of ethylene glycol. Carbonate ions decomposed further with release of carbon dioxide to regenerate alkoxide ion.     

Peptide‐functionalized starPEG/heparin hydrogels direct mitogenicity,cell morphology and cartilage matrix distribution in vitro and in vivo

Cell‐based tissue engineering is a promising approach for treating cartilage lesions, but available strategies still provide a distinct composition of the extracellular matrix and an inferior mechanical property compared to native cartilage. To achieve fully functional tissue replacement more rationally designed biomaterials may be needed, introducing bioactive molecules which modulate cell behavior and guide tissue regeneration. This study aimed at exploring the impact of cell‐instructive, adhesion‐binding (GCWGGRGDSP called RGD) and collagen‐binding (CKLER/CWYRGRL) peptides, incorporated in a tunable, matrixmetalloprotease (MMP)‐responsive multi‐arm poly(ethylene glycol) (starPEG)/heparin hydrogel on cartilage regeneration parameters in vitro and in vivo. MMP‐responsive‐starPEG‐conjugates with cysteine termini and heparin‐maleimide, optionally pre‐functionalized with RGD, CKLER, CWYRGRL or control peptides, were cross‐linked by Michael type addition to embed and grow mesenchymal stromal cells (MSC) or chondrocytes. While starPEG/heparin‐hydrogel strongly supported chondrogenesis of MSC according to COL2A1, BGN and ACAN induction, MMP‐degradability enhanced cell viability and proliferation. RGD‐modification of the gels promoted cell spreading with intense cell network formation without negative effects on chondrogenesis. However, CKLER and CWYRGRL were unable to enhance the collagen content of constructs. RGD‐modification allowed more even collagen type II distribution by chondrocytes throughout the MMP‐responsive constructs, especially in vivo. Collectively, peptide‐instruction via heparin‐enriched MMP‐degradable starPEG allowed adjustment of self‐renewal, cell morphology and cartilage matrix distribution in order to guide MSC and chondrocyte‐based cartilage regeneration towards an improved outcome. Copyright © 2017 John Wiley & Sons, Ltd.     

PEG hydrogel degradation and the role of the surrounding tissue environment

Poly(ethylene glycol) (PEG)‐based hydrogels are extensively used in a variety of biomedical applications, due to ease of synthesis and tissue‐like properties. Recently there have been varied reports regarding PEG hydrogel's degradation kinetics and in vivo host response. In particular, these studies suggest that the surrounding tissue environment could play a critical role in defining the inflammatory response and degradation kinetics of PEG implants. In the present study we demonstrated a potential mechanism of PEG hydrogel degradation, and in addition we show potential evidence of the role of the surrounding tissue environment on producing variable inflammatory responses. Copyright © 2013 John Wiley & Sons, Ltd.     

Bone morphogenetic protein‐2 release profile modulates bone formation in phosphorylated hydrogel

The optimal release profile of locally delivered bone morphogenetic protein‐2 (BMP‐2) for safe and effective clinical application is unknown. In this work, the effect of differential BMP‐2 release on bone formation was investigated using a novel biomaterial oligo[(polyethylene glycol) fumarate] bis[2‐(methacryloyloxy) ethyl] phosphate hydrogel (OPF‐BP) containing poly(lactic‐co‐glycolic acid) microspheres. Three composite implants with the same biomaterial chemistry and structure but different BMP‐loading methods were created: BMP‐2 encapsulated in microspheres (OPF‐BP‐Msp), BMP‐2 encapsulated in microspheres and adsorbed on the phosphorylated hydrogel (OPF‐BP‐Cmb), and BMP‐2 adsorbed on the phosphorylated hydrogel (OPF‐BP‐Ads). These composites were compared with the clinically used BMP‐2 carrier, Infuse® absorbable collagen sponge (ACS). Differential release profiles of bioactive BMP‐2 were achieved by these composites. In a rat subcutaneous implantation model, OPF‐BP‐Ads and ACS generated a large BMP‐2 burst release (>75%), whereas a more sustained release was seen for OPF‐BP‐Msp and OPF‐BP‐Cmb (~25% and 50% burst, respectively). OPF‐BP‐Ads generated significantly more bone than did all other composites, and the bone formation was 12‐fold higher than that of the clinically used ACS. Overall, this study clearly shows that BMP‐2 burst release generates more subcutaneous bone than do sustained release in OPF‐BP‐microsphere composites. Furthermore, composites should not only function as a delivery vehicle but also provide a proper framework to achieve appropriate bone formation.     

Dynamic three‐dimensional micropatterned cell co‐cultures within photocurable and chemically degradable hydrogels

In this paper we report on the development of dynamically controlled three‐dimensional (3D) micropatterned cellular co‐cultures within photocurable and chemically degradable hydrogels. Specifically, we generated dynamic co‐cultures of micropatterned murine embryonic stem (mES) cells with human hepatocellular carcinoma (HepG2) cells within 3D hydrogels. HepG2 cells were used due to their ability to direct the differentiation of mES cells through secreted paracrine factors. To generate dynamic co‐cultures, mES cells were first encapsulated within micropatterned photocurable poly(ethylene glycol) (PEG) hydrogels. These micropatterned cell‐laden PEG hydrogels were subsequently surrounded by calcium alginate (Ca‐Alg) hydrogels containing HepG2 cells. After 4 days, the co‐culture step was halted by exposing the system to sodium citrate solution, which removed the alginate gels and the encapsulated HepG2 cells. The encapsulated mES cells were then maintained in the resulting cultures for 16 days and cardiac differentiation was analysed. We observed that the mES cells that were exposed to HepG2 cells in the co‐cultures generated cells with higher expression of cardiac genes and proteins, as well as increased spontaneous beating. Due to its ability to control the 3D microenvironment of cells in a spatially and temporally regulated manner, the method presented in this study is useful for a range of cell‐culture applications related to tissue engineering and regenerative medicine. Copyright © 2013 John Wiley & Sons, Ltd.     

Preparation of a novel injectable in situ-gelling nanoparticle with applications in controlled protein release and cancer cell entrapment

Temperature sensitive injectable hydrogels have been used as drug/protein carriers for a variety of pharmaceutical applications. Oligo(ethylene glycol) methacrylate (OEGMA) monomers with varying ethylene oxide chain lengths have been used for the synthesis of in situ forming hydrogel. In this study, a new series of thermally induced gelling hydrogel nanoparticles (PMOA hydrogel nanoparticles) was developed by copolymerization with di(ethylene glycol) methyl ether methacrylate (MEO₂MA), poly(ethylene glycol) methyl ether methacrylate (300 g mol⁻¹, OEGMA₃₀₀), and acrylic acid (AAc). The effects of acrylic acid content on the physical, chemical, and biological properties of the nanoparticle-based hydrogels were investigated. Due to its high electrostatic properties, addition of AAc increases LCST as well as gelation temperature. Further, using Cy5-labelled bovine serum albumin and erythropoietin (Epo) as model drugs, studies have shown that the thermogelling hydrogels have the ability to tune the release rate of these proteins in vitro. Finally, the ability of Epo releasing hydrogels to recruit prostate cancer cells was assessed in vivo. Overall, our results support that this new series of thermally induced gelling systems can be used as protein control releasing vehicles and cancer cell traps.

At body temperature, thermosensitive nanoparticles release erythropoietin to lure metastatic cancer cells.