Patterning network structure to spatially control cellular remodeling and stem cell fate within 3-dimensional hydrogels

Khetan, Sudhir; Burdick, Jason A.

doi:10.1016/j.biomaterials.2010.07.035

Cited by 262 publications

(231 citation statements)

References 39 publications

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“…In this work, we used hyaluronic acid (HA), a linear polysaccharide that is composed of alternating d-glucuronic acid and N-acetyl-d-glucosamine, as the primary structural unit, because it is a natural component of the extracellular matrix and is involved in many biological processes 33,34 . HA may be chemically modified in a variety of ways to form hydrogels with tuneable properties (for example, hydrophobicity, degradation) towards the development of biomaterials for tissue engineering and regenerative medicine [34][35][36][37] . Although sequential crosslinking was previously employed to spatially control hydrogel mechanics without cells present, here, for the first time, we report sequential crosslinking as a route for in situ hydrogel stiffening in the presence of cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

2012

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Biological processes are dynamic in nature, and growing evidence suggests that matrix stiffening is particularly decisive during development, wound healing and disease; yet, nearly all in vitro models are static. Here we introduce a step-wise approach, addition then lightmediated crosslinking, to fabricate hydrogels that stiffen (for example, ~3-30 kPa) in the presence of cells, and investigated the short-term (minutes-to-hours) and long-term (daysto-weeks) cell response to dynamic stiffening. When substrates are stiffened, adhered human mesenchymal stem cells increase their area from ~500 to 3,000 µm 2 and exhibit greater traction from ~1 to 10 kPa over a timescale of hours. For longer cultures up to 14 days, human mesenchymal stem cells selectively differentiate based on the period of culture, before or after stiffening, such that adipogenic differentiation is favoured for later stiffening, whereas osteogenic differentiation is favoured for earlier stiffening.

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Section: Resultsmentioning

confidence: 99%

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

2012

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“…A subsequent study combined the click chemistry with a photocleavable functionality, to fabricate spatially patterned hydrogels and then to enable 3D cleavage of crosslinks 30 . Finally, a sequential crosslinking process 31 was used to pattern cell spreading and remodelling by first encapsulating cells in a hydrogel permissive to cell remodelling and then by introducing photo-induced crosslinks. The cells were unable to completely degrade the network, leading to changes in local cell spreading and subsequent stem cell differentiation.…”

Section: Static Hydrogels That Mimic Biophysical Cuesmentioning

confidence: 99%

Moving from static to dynamic complexity in hydrogel design

2012

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Hydrogels are water-swollen polymer networks that have found a range of applications from biological scaffolds to contact lenses. Historically, their design has consisted primarily of static systems and those that exhibit simple degradation. However, advances in polymer synthesis and processing have led to a new generation of dynamic systems that are capable of responding to artificial triggers and biological signals with spatial precision. These systems will open up new possibilities for the use of hydrogels as model biological structures and in tissue regeneration.H ydrogels are water-swollen polymer networks that have been used for many decades, with applications as varied as contact lenses and super-absorbant materials. As the field of biomedical engineering has developed, hydrogels have become a prime candidate for application as molecule delivery vehicles and as carriers for cells in tissue engineering, owing to their ability to mimic many aspects of the native cellular environment (for example, high water content, mechanical properties that match soft tissues). Traditional hydrogels, formed through the covalent and non-covalent crosslinking of polymer chains, were regarded as relatively inert materials, providing a simple biomimetic three-dimensional (3D) environment, either for tissue production by local resident cells or for positioning of cells delivered in vivo. However, the simplicity of these materials may have in fact hindered their application, restricting cellular interactions with the environment and preventing uniform extracellular matrix (ECM) production and proper tissue development. In addition, these materials were limited to modelling static environments and lacked the spatiotemporal dynamic properties relevant for complex tissue processes. Fortunately, during the last decade the concepts of hydrogel design and cellular interaction have evolved, shedding light on how they may control cell behaviour, particularly for tissue engineering applications.Hydrogels with a range of mechanical properties, and capable of incorporating a wide range of biologically relevant molecules, from individual functional groups to multidomain proteins, are currently in development 1 . In addition, hydrogels are being designed with spatial heterogeneity, to either replicate properties in native tissue structures or to produce constructs with distinct regionally specific cell behavior 2 . As a result, studies to date have clearly demonstrated the possibility of creating well-defined microenvironments with control over the 3D presentation of signals to cells 3 . However, recently there has been a focus on the concept of hydrogels that exhibit dynamic complexity. These materials should evolve with time and in response to

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“…Acrylated HA (AHA) hydrogels were prepared as previously reported [36,37]. Briefly, AHA was synthesized using a two-step protocol: (a) the tetrabutylammonium salt of HA (HA-TBA) was formed by reacting sodium hyaluronate (64 kDa; Lifecore Biomedical, Chaska, MN, http://www.lifecore.com) with the highly acidic ion exchange resin Dowex-100 and neutralizing with 0.2 M tetrabutylammonium hydroxide; (b) acrylic acid (2.5 Eq) was coupled to HA-TBA (1 Eq, repeat unit) in the presence of dimethylaminopyridine (0.075 Eq) and di-tert-butyl dicarbonate (1.5 Eq) in dimethyl sulfoxide, followed by dialysis and lyophilization.…”

Section: Synthesis Of Acrylated Ha Hydrogelsmentioning

confidence: 99%

Integration and Regression of Implanted Engineered Human Vascular Networks During Deep Wound Healing

Hanjaya‐Putra

Shen

Wilson

et al. 2013

Stem Cells Translational Medicine

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The ability of vascularized constructs to integrate with tissues may depend on the kinetics and stability of vascular structure development. This study assessed the functionality and durability of engineered human vasculatures from endothelial progenitors when implanted in a mouse deep burn-wound model. Human vascular networks, derived from endothelial colony-forming cells in hyaluronic acid hydrogels, were transplanted into third-degree burns. On day 3 following transplantation, macrophages rapidly degraded the hydrogel during a period of inflammation; through the transitions from inflammation to proliferation (days 5-7), the host's vasculatures infiltrated the construct, connecting with the human vessels within the wound area. The growth of mouse vessels near the wound area supported further integration with the implanted human vasculatures. During this period, the majority of the vessels (ϳ60%) in the treated wound area were human. Although no increase in the density of human vessels was detected during the proliferative phase, they temporarily increased in size. This growth peaked at day 7, the middle of the proliferation stage, and then decreased by the end of the proliferation stage. As the wound reached the remodeling period during the second week after transplantation, the vasculatures including the transplanted human vessels generally regressed, and few microvessels, wrapped by mouse smooth muscle cells and with a vessel area less than 200 m 2 (including the human ones), remained in the healed wound. Overall, this study offers useful insights for the development of vascularization strategies for wound healing and ischemic conditions, for tissue-engineered constructs, and for tissue regeneration. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:297-306

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Patterning network structure to spatially control cellular remodeling and stem cell fate within 3-dimensional hydrogels

Cited by 262 publications

References 39 publications

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

Moving from static to dynamic complexity in hydrogel design

Integration and Regression of Implanted Engineered Human Vascular Networks During Deep Wound Healing

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