Hydrogels are polymer networks infiltrated with water. Many biological hydrogels in animal bodies such as muscles, heart valves, cartilages, and tendons possess extreme mechanical properties including being extremely tough, strong, resilient, adhesive, and fatigue-resistant. These mechanical properties are also critical for hydrogels' diverse applications ranging from drug delivery, tissue engineering, medical implants, wound dressings, and contact lenses to sensors, actuators, electronic devices, optical devices, batteries, water harvesters, and soft robots. Whereas numerous hydrogels have been developed over the last few decades, a set of general principles that can rationally guide the design of hydrogels using different materials and fabrication methods for various applications remain a central need in the field of soft materials. This review is aimed at synergistically reporting: (i) general design principles for hydrogels to achieve extreme mechanical and physical properties, (ii) implementation strategies for the design principles using unconventional polymer networks, and (iii) future directions for the orthogonal design of hydrogels to achieve multiple combined mechanical, physical, chemical, and biological properties. Because these design principles and implementation strategies are based on generic polymer networks, they are also applicable to other soft materials including elastomers and organogels. Overall, the review will not only provide comprehensive and systematic guidelines on the rational design of soft materials, but also provoke interdisciplinary discussions on a fundamental question: why does nature select soft materials with unconventional polymer networks to constitute the major parts of animal bodies?

Soft Materials by Design: Unconventional Polymer Networks Give Extreme Properties.

Graphene Oxide-Templated Conductive and Redox-Active Nanosheets Incorporated Hydrogels for Adhesive Bioelectronics

Exocytosis and endocytosis

Injectable hydrogels have received considerable interest in the biomedical field due to their potential applications in minimally invasive local drug delivery, more precise implantation, and site-specific drug delivery into poorly reachable tissue sites and into interface tissues, where wound healing takes a long time. Injectable hydrogels, such as in situ forming and/or shear-thinning hydrogels, can be generated using chemically and/or physically crosslinked hydrogels. Yet, for controlled and local drug delivery applications, the ideal injectable hydrogel should be able to provide controlled and sustained release of drug molecules to the target site when needed and should limit nonspecific drug molecule distribution in healthy tissues. Thus, such hydrogels should sense the environmental changes that arise in disease states and be able to release the optimal amount of drug over the necessary time period to the target region. To address this, researchers have designed stimuli-responsive injectable hydrogels. Stimuli-responsive hydrogels change their shape or volume when they sense environmental stimuli, e.g., pH, temperature, light, electrical signals, or enzymatic changes, and deliver an optimal concentration of drugs to the target site without affecting healthy tissues.

Recent Advances in Injectable Hydrogels for Controlled and Local Drug Delivery

Tendon injuries cause prolonged disability and never recover completely. Current mechanistic understanding of tendon regeneration is limited. Here, we use single-cell transcriptomics to identify a tubulin polymerization-promoting protein family member 3-expressing (Tppp3+) cell population as potential tendon stem cells. Through inducible lineage tracing, we demonstrate that these cells can generate new tenocytes and self-renew upon injury. A fraction of Tppp3+ cells expresses platelet-derived growth factor receptor alpha (Pdfgra). Ectopic platelet-derived growth factor-AA (PDGF-AA) protein induces new tenocyte production while inactivation of Pdgfra in Tppp3+ cells blocks tendon regeneration. These results support Tppp3+Pdgfra+ cells as tendon stem cells. Unexpectedly, Tppp3-Pdgfra+ fibro-adipogenic progenitors coexist in the tendon stem cell niche and give rise to fibrotic cells, revealing a clandestine origin of fibrotic scars in healing tendons. Our results explain why fibrosis occurs in injured tendons and present clinical challenges to enhance tendon regeneration without a concurrent increase in fibrosis by PDGF application.

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A Tppp3 + Pdgfra + tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis

Poly(ethylene glycol) (PEG)-based hydrogels are promising materials for biomedical applications because of their excellent hydrophilicity and biocompatibility. However, conventional chemically cross-linked PEG hydrogels are brittle under mechanical loading. The mechanical resilience and rapid recovery abilities of hydrogel implants are critical in load-bearing tissues, such as articular cartilage, which are routinely subjected to cyclic loadings of high magnitude and frequency. Here, we report the fabrication of novel supramolecular PEG hydrogels by polymerizing N,N-dimethylacrylamide with supramolecular cross-linkers self-assembled from adamantane-grafted PEG and mono-acrylated β-cyclodextrin. The resultant PEG–ADA supramolecular hydrogels exhibit substantial deformability, excellent capacity to dissipate massive amounts of loading energy, and have a rapid, full recovery during excessive, ultrafast, and non-resting cyclic compression. Furthermore, the energy dissipation capacity of the PEG–ADA (adamantane-grafted Poly(ethylene glycol)) hydrogels can be regulated by changing the concentration, molecular weight and cross-linking density of PEG. According to in vitro cell metabolism and viability tests, the PEG–ADA hydrogels are non-cytotoxic. When placed over a monolayer of myoblasts that were subjected to instantaneous compressive loading, the PEG–ADA hydrogel cushion significantly enhanced cell survival under this deleterious mechanical insult compared with the effects of the conventional PEG hydrogel. Therefore, PEG–ADA hydrogels are promising prosthetic biomaterials for the repair and regeneration of load-bearing tissues. Soft, water-filled polymers known as hydrogels may find roles as implants in load-bearing joints thanks to advances in strain-resistant chemical networks. Most hydrogels contain molecular components called cross-links that connect long polymer chains into a sturdy network. A team led by Bin Li at China’s Soochow University in Suzhou and Liming Bian at the Chinese University of Hong Kong have developed a hydrogel cross-linking system based on a pair of molecules, cyclodextrin and adamantine, that attach to each other using physical forces instead of conventional chemical bonds. When exposed to a mechanical load, these cross-links quickly separate to dissipate energy, then re-associate to preserve the original gel network. Compression experiments revealed the new material could cushion the force applied to mouse muscle cell cultures and reduced cell death rates by 30% compared with conventional hydrogels. This study is to investigate and systemically study the mechanical performance of supramolecular PEG hydrogels in comparison with those of the chemical hydrogels cross-linked by conventional PEG diacrylate (PEGDA). The supramolecular cross-links based on the host-guest complexation significantly enhance the energy dissipation, fatigue resistance, and stress-relaxation of supramolecular PEG hydrogels and protect cells from deleterious mechanical insults. This research provides valuable guidance on the design of prosthetic hydrogels for loading bearing implantations sites with surrounding mechanosensitive cells or tissues and critical insights on the translation of host-guest hydrogels to biomedical applications.

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Supramolecular hydrogels cross-linked by preassembled host–guest PEG cross-linkers resist excessive, ultrafast, and non-resting cyclic compression

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

Arterial baroreceptors are mechanical sensors that detect blood pressure changes. It has long been suggested that the two arterial baroreceptors, aortic and carotid baroreceptors, have different pressure sensitivities. However, there is no consensus as to which of the arterial baroreceptors are more sensitive to changes in blood pressure. In the present study, we employed independent methods to compare the pressure sensitivity of the two arterial baroreceptors. Firstly, pressure-activated action potential firing was measured by whole-cell current clamp with a high-speed pressure clamp system in primary cultured baroreceptor neurons. The results show that aortic depressor neurons possessed a higher percentage of mechano-sensitive neurons. Furthermore, aortic baroreceptor neurons show a lower pressure threshold than that of carotid baroreceptor neurons. Secondly, uniaxial stretching of baroreceptor neurons, that mimics the forces exerted on blood vessels, elicited a larger increase in intracellular Ca2+ rise in aortic baroreceptor neurons than in carotid baroreceptor neurons. Thirdly, the pressure-induced action potential firing in the aortic depressor nerve recorded in vivo was also higher. The present study therefore provides for a basic physiological understanding on the pressure sensitivity of the two baroreceptor neurons and suggests that aortic baroreceptors have a higher pressure sensitivity than carotid baroreceptors.

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Aortic Baroreceptors Display Higher Mechanosensitivity than Carotid Baroreceptors

Many investigations into the interactions between nanoparticles and mammalian cells entail the use of culture systems that do not account for the effect of extracellular mechanical cues, such as compression. In this work, we present an experimental set-up to systematically investigate the combined effects of nanoparticle size and compressive stress on the cellular uptake and intracellular localization of poly(ethylene glycol)-coated gold nanoparticles (Au-PEG NPs). Specifically, we employ an automated micromechanical system to apply defined levels of compressive strain to an agarose gel, which transmits defined amounts of unconfined, uniaxial compressive stress to a monolayer of C2C12 mouse myoblasts seeded underneath the gel without compromising cell viability. Notably, uptake of Au-PEG NPs smaller than 25 nm by compressed myoblasts is up to 5-fold higher than that by uncompressed cells. The optimal compressive stress for maximizing the cellular uptake of sub-25 nm NPs monotonically increases with NP size. With and without compression, the Au-PEG NPs enter C2C12 cells via energy-dependent uptake; they also enter compressed cells via clathrin-mediated endocytosis as the major pathway. Upon cellular entry, the Au-PEG NPs more readily reside in the late endosomes or lysosomes of compressed cells than uncompressed cells. Results from our experimental set-up yield mechanistic insights into the delivery of NPs to cell types under extracellular compression.

Arthur Fuk-Tat Mak

Papers

Supramolecular hydrogels cross-linked by preassembled host–guest PEG cross-linkers resist excessive, ultrafast, and non-resting cyclic compression

Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

Aortic Baroreceptors Display Higher Mechanosensitivity than Carotid Baroreceptors

Promoting intracellular delivery of sub-25 nm nanoparticles via defined levels of compression