Publications

Skin injuries across the body continue to disrupt everyday life for millions of patients and result in prolonged hospital stays, infection, and death. Advances in wound healing devices have improved clinical practice but have mainly focused on treating macroscale healing versus underlying microscale pathophysiology. Consensus is lacking on optimal treatment strategies using a spectrum of wound healing products, which has motivated the design of new therapies. We summarize advances in the development of novel drug, biologic products, and biomaterial therapies for wound healing for marketed therapies and those in clinical trials. We also share perspectives for successful and accelerated translation of novel integrated therapies for wound healing.

Extracellular matrices composed of collagen provide structural support to soft tissues and have an impact on cellular behavior, including the cells responsible for producing and modifying the matrix. The mechanobiological effects of matrix on cells have emerged as important factors in driving the behavior of pathogens, immune cells, neurons, stem cells, and cancer cells. Improving our understanding of collagen mechanobiology has the potential to advance research across organ systems in health and the myriad of fibrotic disease conditions which disrupt the collagen network.

This Research Topic includes articles that reflect the major challenges and open questions in the collagen mechanobiology field today: the impact of mechanics on collagen degradation and synthesis, the relationship between collagen structure and function, and the best modalities for imaging collagen at different length scales.

Robot-actuated mechanical loading (ML)–based therapies (“mechanotherapies”) can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are common chronic inflammatory conditions, manifesting as painful oral lesions that negatively affect patients’ quality of life. Current treatment approaches are mainly palliative and often ineffective due to inadequate contact time of the therapeutic agent with the lesions. Here, we developed the Dental Tough Adhesive (DenTAl), a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended drug delivery of clobetasol-17-propionate, a first-line drug for treating OLP and RAS. DenTAl was found to have superior physical and adhesive properties compared to existing oral technologies, with  2 to 100× adhesion to porcine keratinized gingiva and  3 to 15× stretchability. Clobetasol-17-propionate incorporated into the DenTAl was released in a tunable sustained manner for at least 3 wk and demonstrated immunomodulatory capabilities in vitro, evidenced by reductions in several cytokines, including TNF-α, IL-6, IL-10, MCP-5, MIP-2, and TIMP-1. Our findings suggest that DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful oral lesions associated with chronic inflammatory conditions.

Multicellular spheroids made of stem cells can act as building blocks that fuse to capture complex aspects of native in vivo environments, but the effect of hydrogel viscoelasticity on cell migration from spheroids and their fusion remains largely unknown. Here, we investigated the effect of viscoelasticity on migration and fusion behavior of mesenchymal stem cell (MSC) spheroids using hydrogels with a similar elasticity but different stress relaxation profiles. Fast relaxing (FR) matrices were found to be significantly more permissive to cell migration and consequent fusion of MSC spheroids. Mechanistically, inhibition of ROCK and Rac1 pathways prevented cell migration. Moreover, the combination of biophysical and biochemical cues provided by fast relaxing hydrogels and platelet-derived growth factor (PDGF) supplementation, respectively, resulted in a synergistic enhancement of migration and fusion. Overall, these findings emphasize the important role of matrix viscoelasticity in tissue engineering and regenerative medicine strategies based on spheroids.

Lymph nodes (LNs) dynamically expand in response to immunization, but the relationship between LN expansion and the accompanying adaptive immune response is unclear. Here, we first characterized the LN response across time and length scales to vaccines of distinct strengths. High-frequency ultrasound revealed that a bolus ‘weak’ vaccine induced a short-lived, 2-fold volume expansion, while a biomaterial-based ‘strong’ vaccine elicited an ∼7-fold LN expansion, which was maintained several weeks after vaccination. This latter expansion was associated with altered matrix and mechanical properties of the LN microarchitecture. Strong vaccination resulted in massive immune and stromal cell engagement, dependent on antigen presence in the vaccine, and conventional dendritic cells and inflammatory monocytes upregulated genes involved in antigen presentation and LN enlargement. The degree of LN expansion following therapeutic cancer vaccination strongly correlated with vaccine efficacy, even 100 days post-vaccination, and direct manipulation of LN expansion demonstrated a causative role in immunization outcomes.

Hydrogel-based drug delivery systems typically aim to release drugs locally to tissue in an extended manner. Tissue adhesive alginate-polyacrylamide tough hydrogels are recently demonstrated to serve as an extended-release system for the corticosteroid triamcinolone acetonide. Here, the stimuli-responsive controlled release of triamcinolone acetonide from the alginate-polyacrylamide tough hydrogel drug delivery systems (TADDS) and evolving new approaches to combine alginate-polyacrylamide tough hydrogel with drug-loaded nano and microparticles, generating composite TADDS is described. Stimulation with ultrasound pulses or temperature changes is demonstrated to control the release of triamcinolone acetonide from the TADDS. The incorporation of laponite nanoparticles or PLGA microparticles into the tough hydrogel is shown to further enhance the versatility to control and modulate the release of triamcinolone acetonide. A first technical exploration of a TADDS shelf-life concept is performed using lyophilization, where lyophilized TADDS are physically stable and the bioactive integrity of released triamcinolone acetonide is demonstrated. Given the tunability of properties, the TADDS are a suggested technology platform for controlled drug delivery.

Approved therapies for tendon diseases have not yet changed the clinical practice of symptomatic pain treatment and physiotherapy. This review article summarizes advances in the development of novel drugs, biologic products, and biomaterial therapies for tendon diseases with perspectives for translation of integrated therapies. Shifting from targeting symptom relief toward disease modification and prevention of disease progression may open new avenues for therapies. Deep evidence-based clinical, cellular, and molecular characterization of the underlying pathology of tendon diseases, as well as therapeutic delivery optimization and establishment of multidiscipline interorganizational collaboration platforms, may accelerate the discovery and translation of transformative therapies for tendon diseases.

Tissue adhesives capable of achieving strong and tough adhesion in permeable wet environments are useful in many biomedical applications. However, adhesion generated through covalent bond formation directly with the functional groups of tissues (i.e., -COOH and -NH₂ groups in collagen), or using non-covalent interactions can both be limited by weak, unstable, or slow adhesion. Here, it is shown that by combining pH-responsive bridging chitosan polymer chains and a tough hydrogel dissipative matrix one can achieve unprecedented ultratough adhesion to tissues (>2000 J m⁻²) in 5–10 min without covalent bond formation. The strong non-covalent adhesion is shown to be stable under physiologically relevant conditions and strongly influenced by chitosan molecular weight, molecular weight of polymers in the matrix, and pH. The adhesion mechanism relies primarily on the topological entanglement between the chitosan chains and the permeable adherends. To further expand the applicability of the adhesives, adhesion time can be decreased by dehydrating the hydrogel matrix to facilitate rapid chitosan interpenetration and entanglement (>1000 J m⁻² in ≤1 min). The unprecedented adhesive properties presented in this study open opportunities for new strategies in the development of non-covalent tissue adhesives and numerous bioapplications.

Aging is the largest risk factor for Achilles tendon associated disorders and rupture. Although Achilles tendon macroscale elastic properties are suggested to decline with aging, less is known about the effect of maturity and aging on multiscale viscoelastic properties and their effect on tendon cell behavior. Here, we show dose dependent changes in native multiscale tendon mechanical and structural properties and uncover several nanoindentation properties predicted by tensile mechanics and echogenicity. Alginate hydrogel systems designed to mimic juvenile tendon microscale mechanics revealed that stiffness and viscoelasticity affected Achilles tendon cell aspect ratio and proliferation during aging. This knowledge provides further evidence for the negative impact of maturity and aging on tendon and begins to elucidate how viscoelasticity can control tendon derived cell morphology and expansion.