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Inflammation-driven foreign body reactions, and the frequently associated encapsulation by fibrogenic fibroblasts, reduce the functionality and longevity of implanted medical devices and materials. Anti-inflammatory drugs, such as dexamethasone, can suppress the foreign body reaction for a few days post-surgery, but lasting drug delivery strategies for long-term implanted materials remain an unmet need. We here establish a thin-coating strategy with novel low molecular weight corticosteroid dimers to suppress foreign body reactions and fibrotic encapsulation of subcutaneous silicone implants. The dimer coatings are >75% dexamethasone by mass and directly processable into conformal coatings using conventional solvent-based techniques, such as casting or spray coating without added polymers or binding agents. In vitro, surface erosion of the coating, and subsequent hydrolysis, provide controlled release of free dexamethasone. In a rat subcutaneous implantation model, the resulting slow and sustained release profile of dexamethasone is effective at reducing the number and activation of pro-fibrotic macrophages both acutely and at chronic time points. Consequently, fibroblast activation, collagen deposition and fibrotic encapsulation are suppressed at least 45 days post-implantation. Thus, our approach to protect implants from host rejection is advantageous over polymeric drug delivery systems, which typically have low drug loading capacity (<30%), initial burst release profiles, and unpredictable release kinetics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Stem cells in their microenvironment are exposed to a plethora of biochemical signals and biophysical forces. Interrogating the role of each factor in the cell microenvironment, however, remains difficult due to the inability to study microenvironmental cues and tease apart their interactions in high throughput. To address this need, we developed an extracellular matrix (ECM) microarray screening platform capable of tightly controlling substrate stiffness and ECM protein composition to screen the effects of these cues and their interactions on cell fate. We combined this platform with a design of experiments screening strategy to identify optimal conditions that can maintain human pluripotent stem cell (hPSC) pluripotency in chemically defined, xeno-free conditions. Combinations of ECM proteins (fibronectin, vitronectin, laminin-521, and collagen IV) were deposited on polydimethylsiloxane substrates with elastic moduli ranging from ~1 to 60 kPa using a high throughput protein plotter. Through our screening approach, we identified several non-intuitive protein-protein and protein-stiffness interactions and developed three novel culture substrates. hPSCs grown on these novel culture substrates displayed higher proliferation rates and pluripotency marker expression than current gold-standard culture substrates Geltrex- and vitronectin-coated plastic. This ECM microarray and screening approach is not limited to the factors studied here and can be broadly applied to other cell types to systematically screen microenvironmental conditions to optimally guide cell phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Over the past decade, various implantable devices have been developed to treat diseases that were previously difficult to manage such diabetes, chronic pain, and neurodegenerative disorders. However, translation of these novel technologies into clinical practice is often difficult because fibrotic encapsulation and/or rejection impairs device function after body implantation. Ideally, cells of the host tissue should perceive the surface of the implant being similar to the normal extracellular matrix. Here, we developed an innovative approach to provide implant surfaces with adhesive protein micropatterns. The patterns were designed to promote adhesion of fibroblasts and macrophages by simultaneously suppressing fibrogenic activation of both cell types. In a rat model, subcutaneously implanted silicone pads provided with the novel micropatterns caused 6-fold lower formation of inflammatory giant cells compared with clinical grade, uncoated, or collagen-coated silicone implants. We further show that micropatterning of implants resulted in 2-3-fold reduced numbers of pro-fibrotic myofibroblast by inhibiting their mechanical activation. Our novel approach allows controlled cell attachment to implant surfaces, representing a critical advance for enhanced biointegration of implantable medical devices., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Strain devices with expandable polydimethylsiloxane (PDMS) culture membranes are frequently used to stretch cells in vitro, mimicking mechanically dynamic tissue environments. To immobilize cell-adhesive molecules to the otherwise non-adhesive PDMS substrate, hydrophobic, electrostatic and covalent surface coating procedures have been developed. The efficacy of different coating strategies to transmit stretches to cells however is poorly documented and has not been compared. We describe a novel and simple procedure to covalently bind extracellular matrix proteins to the surface of stretchable PDMS membranes. The method comprises PDMS oxygenation, silanization, and covalent protein cross-linking to the silane. We demonstrate improved attachment ( approximately 2-fold), spreading ( approximately 2.5-fold) and proliferation ( approximately 1.2-fold) of fibroblasts to our new coating over established coating procedures. Further, we compared the efficiency of different PDMS coating techniques to transmit stretches. After 15% stretch, the number of maximally (15 +/- 5%) stretched cells on our PDMS surface coating was approximately 7-fold higher compared with alternative coating protocols. Hence, covalent linkage of adhesive molecules is superior to non-covalent methods in providing a coating that resists large deformations and that fully transmit this stretch to cultured cells.

Surface properties of implanted biomaterials can cause fibrotic tissue reactions by stimulating differentiation of host fibroblasts into contractile myofibroblasts. Silk fibroin (SF) protein has been used as biomaterial in pure and blended form. however, its effect on myofibroblast differentiation remains elusive. We here conjugated SF with lactose using cyanuric chloride as coupling spacer. NMR spectroscopy and the conjugates ability to agglomerate Abrus precatorius agglutinin verified efficient conjugation. Two-dimensional films and three-dimensional scaffolds produced from pure and lactose-conjugated SF solutions were tested as culture substrates for subcutaneous fibroblasts and myofibroblasts. Lactose-conjugated SF substrates mediated higher adhesion, proliferation and viability of fibroblastic cells than pure SF. This SF film composition promotes better attachment of fibroblasts than myofibroblasts. Pro-fibrotic cytokine TGFbeta1 was ineffective in inducing fibroblast-to-myofibroblast differentiation on such substrates. Pre-differentiated myofibroblasts lost their contractile phenotype within a few days of being cultured on lactose-conjugated SF. Myofibroblast differentiation was also suppressed by growth in three-dimensional lactose-conjugated SF scaffolds that, however, support population with fibroblasts. We propose that this biomaterial will promote tissue integration without causing a fibrotic host reaction.