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Item Biomimetic stiffening of cell-laden hydrogels via sequential thiol-ene and hydrazone click reactions(Elsevier, 2021) Chang, Chun-Yi; Johnson, Hunter C.; Babb, Olivia; Fishel, Melissa L.; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyHydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer – gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). The unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment.Item Delivery of interleukin-10 via injectable hydrogels improves renal outcomes and reduces systemic inflammation following ischemic acute kidney injury in mice(American Physiological Society, 2016-08) Soranno, Danielle E.; Rodell, Christopher B.; Altmann, Christopher; Duplantis, Jane; Andres-Hernando, Ana; Burdick, Jason A.; Faubel, Sarah; Pediatrics, School of MedicineInjectable hydrogels can be used to deliver drugs in situ over a sustained period of time. We hypothesized that sustained delivery of interleukin-10 (IL-10) following acute kidney injury (AKI) would mitigate the local and systemic proinflammatory cascade induced by AKI and reduce subsequent fibrosis. Wild-type C57BL/6 mice underwent ischemia-reperfusion AKI with avertin anesthesia. Three days later, mice were treated with either hyaluronic acid injectable hydrogel with or without IL-10, or IL-10 suspended in saline, injected under the capsule of the left kidney, or hydrogel with IL-10 injected subcutaneously. Untreated AKI served as controls. Serial in vivo optical imaging tracked the location and degradation of the hydrogel over time. Kidney function was assessed serially. Animals were killed 28 days following AKI and the following were evaluated: serum IL-6, lung inflammation, urine neutrophil gelatinase-associated lipocalin, and renal histology for fibroblast activity, collagen type III deposition and fibrosis via Picrosirius Red staining and second harmonic imaging. Our model shows persistent systemic inflammation, and renal inflammation and fibrosis 28 days following AKI. The hydrogels are biocompatible and reduced serum IL-6 and renal collagen type III 28 days following AKI even when delivered without IL-10. Treatment with IL-10 reduced renal and systemic inflammation, regardless of whether the IL-10 was delivered in a sustained manner via the injectable hydrogel under the left kidney capsule, as a bolus injection via saline under the left kidney capsule, or via the injectable hydrogel subcutaneously. Injectable hydrogels are suitable for local drug delivery following renal injury, are biocompatible, and help mitigate local and systemic inflammation.Item Heparinized Gelatin-Based Hydrogels for Differentiation of Induced Pluripotent Stem Cells(American Chemical Society, 2022) Arkenberg, Matthew R.; Koehler, Karl; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyChemically defined hydrogels are increasingly utilized to define the effects of extracellular matrix (ECM) components on cellular fate determination of human embryonic and induced pluripotent stem cell (hESC and hiPSCs). In particular, hydrogels cross-linked by orthogonal click chemistry, including thiol-norbornene photopolymerization and inverse electron demand Diels-Alder (iEDDA) reactions, are explored for 3D culture of hESC/hiPSCs owing to the specificity, efficiency, cytocompatibility, and modularity of the cross-linking reactions. In this work, we exploited the modularity of thiol-norbornene photopolymerization to create a biomimetic hydrogel platform for 3D culture and differentiation of hiPSCs. A cell-adhesive, protease-labile, and cross-linkable gelatin derivative, gelatin-norbornene (GelNB), was used as the backbone polymer for constructing hiPSC-laden biomimetic hydrogels. GelNB was further heparinized via the iEDDA click reaction using tetrazine-modified heparin (HepTz), creating GelNB-Hep. GelNB or GelNB-Hep was modularly cross-linked with either inert macromer poly(ethylene glycol)-tetra-thiol (PEG4SH) or another bioactive macromer-thiolated hyaluronic acid (THA). The formulations of these hydrogels were modularly tuned to afford biomimetic matrices with similar elastic moduli but varying bioactive components, enabling the understanding of each bioactive component on supporting hiPSC growth and ectodermal, mesodermal, and endodermal fate commitment under identical soluble differentiation cues.Item Hyaluronic acid as an adjunct to microfracture in the treatment of osteochondral lesions of the talus: a systematic review of randomized controlled trials(BMC, 2022-04-02) Dilley, Julian E.; Everhart, Joshua S.; Klitzman, Robert G.; Orthopaedic Surgery, School of MedicineBackground: Osteochondral lesions of the talus (OLT) are common after ankle trauma. Studies have shown that bioactive substances, such as hyaluronic acid (HA), alone, or in combination, with surgical treatment could improve cartilage regeneration and repair, but the effect of HA on patient reported outcomes is unclear. Methods: Literature searches were performed across four databases (PubMed, SPORTDiscus, Scopus, and The Cochrane Library) for randomized controlled trials in which at least one treatment arm involved use of HA as an adjunct to microfracture to treat patients with OLT. Primary outcomes included the American Orthopaedic Foot and Ankle Society scores (AOFAS), and the Visual Analog Scale (VAS) for pain. The level of evidence and methodological quality were evaluated using the Modified Coleman Methodology Score (MCMS). Results: Three randomized studies were eligible for review with a total of 132 patients (35, 40, 57 patients, respectively) and follow-up ranged from 10.5 to 25 months. Utilization of HA at the time of microfracture resulted in greater improvement in AOFAS scores compared to microfracture alone. The pooled effect size was moderate (Standardized Mean Difference [SMD] 0.45, 95% Confidence Interval [CI] 0.06, 0.84; P = .02) and between-study heterogeneity was low (I-squared = 0%). Utilization of HA during microfracture also led to greater improvement in VAS-pain scores compared to microfracture alone. The pooled effect size was very large (SMD -3.86, 95% CI -4.75, - 2.97; P < .001) and heterogeneity was moderate (I-squared = 69%). Conclusion: Hyaluronic acid injection as an adjunct to arthroscopic MF in OLT provides clinically important improvements in function and pain at short-term follow-up compared to MF alone. Future longer-term follow-up studies are warranted to investigate the durability of MF with HA for treatment of OLT.Item Hyaluronic acid–binding insulin-like growth factor-1: Creation of a gene encoding a bifunctional fusion protein(Springer, 2020-12) Shi, Shuiliang; Wang, Congrong; Trippel, Stephen B.; Orthopaedic Surgery, School of MedicineChondrogenic growth factors are promising therapeutic agents for articular cartilage repair. A persistent impediment to fulfilling this promise is a limited ability to apply and retain the growth factors within the region of cartilage damage that is in need of repair. Current therapies successfully deliver cells and/or matrices, but growth factors are subject to diffusion into the joint space and then loss from the joint. To address this problem, we created a novel gene that encodes a bifunctional fusion protein comprised by a matrix binding domain and a growth factor. The gene encodes the hyaluronic acid binding region of the cartilage matrix molecule, versican, and the chondrogenic growth factor, insulin-like growth factor-1 (IGF-1). We delivered the gene in an adeno-associated virus-based plasmid vector to articular chondrocytes. The cells synthesized and secreted the fusion protein gene product. The fusion protein bound to hyaluronic acid and retained the anabolic and mitogenic actions of IGF-1 on the chondrocytes. This proof-of-concept study suggests that the bifunctional fusion protein, in concert with chondrocytes and a hyaluronic acid-based delivery vehicle, may serve as an intra-articular therapy to help achieve articular cartilage repair.Item Intravascular heavy chain-modification of hyaluronan during endotoxic shock(Elsevier, 2018-12-26) Ni, Kevin; Gill, Amar; Cao, Danting; Koike, Kengo; Schweitzer, Kelly S.; Garantziotis, Stavros; Petrache, Irina; Biochemistry and Molecular Biology, School of MedicineDuring inflammation, the covalent linking of the ubiquitous extracellular polysaccharide hyaluronan (HA) with the heavy chains (HC) of the serum protein inter alpha inhibitor (IαI) is exclusively mediated by the enzyme tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6). While significant advances have been made regarding how HC-modified HA (HC-HA) is an important regulator of inflammation, it remains unclear why HC-HA plays a critical role in promoting survival in intraperitoneal lipopolysaccharide (LPS)-induced endotoxemia while exerting only a modest role in the outcomes following intratracheal exposure to LPS. To address this gap, the two models of intraperitoneal LPS-induced endotoxic shock and intratracheal LPS-induced acute lung injury were directly compared in TSG-6 knockout mice and littermate controls. HC-HA formation, endogenous TSG-6 activity, and inflammatory markers were assessed in plasma and lung tissue. TSG-6 knockout mice exhibited accelerated mortality during endotoxic shock. While both intraperitoneal and intratracheal LPS induced HC-HA formation in lung parenchyma, only systemically-induced endotoxemia increased plasma TSG-6 levels and intravascular HC-HA formation. Cultured human lung microvascular endothelial cells secreted TSG-6 in response to both TNFα and IL1β stimulation, indicating that, in addition to inflammatory cells, the endothelium may secrete TSG-6 into circulation during systemic inflammation. These data show for the first time that LPS-induced systemic inflammation is uniquely characterized by significant vascular induction of TSG-6 and HC-HA, which may contribute to improved outcomes of endotoxemia.Item Measurement of glomerular filtration rate reveals that subcapsular injection of shear‐thinning hyaluronic acid hydrogels does not impair kidney function in mice(Wiley, 2022-03) Soranno, Danielle E.; Kirkbride-Romeo, Lara; Han, Daniel; Altmann, Christopher; Rodell, Christopher B.; Pediatrics, School of MedicineThe continued development of minimally invasive therapeutic implants, such as injectable hydrogels, necessitates the concurrent advancement of methods to best assess their biocompatibility via functional outcomes in vivo. Biomaterial implants have been studied to treat kidney disease; however, assessment of biocompatibility has been limited to biomarker and histological assessments. Techniques now exist to measure kidney function serially in vivo in murine studies via transcutaneous measurements of glomerular filtration rate (tGFR). In this study, adult male and female wild-type BalbC mice underwent right unilateral nephrectomy. The remaining solitary left kidney was allowed 4 weeks to recover via compensatory hypertrophy, after which subcapsular injection of either saline or shear-thinning hyaluronic acid hydrogel was performed. Serial tGFR measurements before and after treatment were used to assess the effect of hydrogel injection on kidney filtration. Urine and serum biomarkers of kidney function, and kidney histology were also quantified. Hydrogel injection did not affect kidney function, as assessed by tGFR. Results were in agreement with standard metrics of serum and urine biomarkers of injury as well as histological assessment of inflammation. The model developed provides a direct functional assessment of implant compatibility for the treatment of kidney disease and impact on kidney function.Item Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury(BMC, 2018-05-31) Ni, Kevin; Gill, Amar; Tseng, Victor; Mikosz, Andrew M.; Koike, Kengo; Beatman, Erica L.; Xu, Cassie Y.; Cao, Danting; Gally, Fabienne; Mould, Kara J.; Serban, Karina A.; Schweitzer, Kelly S.; March, Keith L.; Janssen, William J.; Nozik-Grayck, Eva; Garantziotis, Stavros; Petrache, Irina; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Several inflammatory lung diseases display abundant presence of hyaluronic acid (HA) bound to heavy chains (HC) of serum protein inter-alpha-inhibitor (IαI) in the extracellular matrix. The HC-HA modification is critical to neutrophil sequestration in liver sinusoids and to survival during experimental lipopolysaccharide (LPS)-induced sepsis. Therefore, the covalent HC-HA binding, which is exclusively mediated by tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6), may play an important role in the onset or the resolution of lung inflammation in acute lung injury (ALI) induced by respiratory infection. METHODS: Reversible ALI was induced by a single intratracheal instillation of LPS or Pseudomonas aeruginosa in mice and outcomes were studied for up to six days. We measured in the lung or the bronchoalveolar fluid HC-HA formation, HA immunostaining localization and roughness, HA fragment abundance, and markers of lung inflammation and lung injury. We also assessed TSG-6 secretion by TNFα- or LPS-stimulated human alveolar macrophages, lung fibroblast Wi38, and bronchial epithelial BEAS-2B cells. RESULTS: Extensive HC-modification of lung HA, localized predominantly in the peri-broncho-vascular extracellular matrix, was notable early during the onset of inflammation and was markedly decreased during its resolution. Whereas human alveolar macrophages secreted functional TSG-6 following both TNFα and LPS stimulation, fibroblasts and bronchial epithelial cells responded to only TNFα. Compared to wild type, TSG-6-KO mice, which lacked HC-modified HA, exhibited modest increases in inflammatory cells in the lung, but no significant differences in markers of lung inflammation or injury, including histopathological lung injury scores. CONCLUSIONS: Respiratory infection induces rapid HC modification of HA followed by fragmentation and clearance, with kinetics that parallel the onset and resolution phase of ALI, respectively. Alveolar macrophages may be an important source of pulmonary TSG-6 required for HA remodeling. The formation of HC-modified HA had a minor role in the onset, severity, or resolution of experimental reversible ALI induced by respiratory infection with gram-negative bacteria.Item Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting(Sage, 2021) Ong, Kevin L.; Farr, Jack; Gudeman, Andrew S.; Murray, Iain R.; McIntyre, Louis F.; Hummer, Charles D.; Ngai, Wilson; Lau, Edmund; Altman, Roy D.; Sherman, Seth L.; Orthopaedic Surgery, School of MedicineObjective: Case reports of severe acute localized reactions (SALR) following intraarticular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products. Design: Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users, matched by single or multiple injection products. Occurrences of surrogate SALR measures including inflammation/infection, intraarticular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, and arthroscopy were evaluated within 3 days post-HA. Results: Based on 694,404 HA injections, inflammation/infection rate was rare within 3 days of HA (up to 0.03%), with no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups (matched by single or multiple injection products). The risk of knee arthrotomy/incision and drainage, arthroscopy, or arthrocentesis for hylan G-F 20 (2 mL) 3 weekly injection patients was lower than Hyalgan/Supartz and Orthovisc patients, but greater than Euflexxa patients. Overall, we found that Hylan G-F 20 (2 mL) 3 weekly injection had lower SALR rates compared to Hyalgan/Supartz and Orthovisc. However, Hylan G-F 20 (2 mL) 3 weekly injection had slightly higher rates of SALR when compared to Euflexxa. Among the single injection products, Hylan G-F 20 (6 mL) single injection had lower rates of SALR than Monovisc and Gel-One. Conclusions: This study shows no clear correlation between avian-derived or cross-linked products and SALR and provides evidence against avian-derived products or crosslinking as a source for these reactions.