Advances in Stimuli-responsive Hydrogels for Tissue Engineering and Regenerative Medicine Applications: A Review Towards Improving Structural Design for 3D Printing.

The physicochemical properties of polymeric hydrogels render them attractive for the development of 3D printed prototypes for tissue engineering in regenerative medicine. Significant effort has been made to design hydrogels with desirable attributes that facilitate 3D printability. In addition, there is significant interest in exploring stimuli-responsive hydrogels to support automated 3D printing into more structurally organised prototypes such as customizable bio-scaffolds for regenerative medicine applications. Synthesizing stimuli-responsive hydrogels is dependent on the type of design and modulation of various polymeric materials to open novel opportunities for applications in biomedicine and bio-engineering. In this review, the salient advances made in the design of stimuli-responsive polymeric hydrogels for 3D printing in tissue engineering are discussed with a specific focus on the different methods of manipulation to develop 3D printed stimuli-responsive polymeric hydrogels. Polymeric functionalisation, nano-enabling and crosslinking are amongst the most common manipulative attributes that affect the assembly and structure of 3D printed bio-scaffolds and their stimuli- responsiveness. The review also provides a concise incursion into the various applications of stimuli to enhance the automated production of structurally organized 3D printed medical prototypes.

Tannic acid-loaded chitosan-RGD-alginate scaffolds for wound healing and skin regeneration.

Hydrogels have drawn much attention in the field of tissue regeneration and wound healing owing to the application of biocompatible peptides to tailor structural features necessitating optimal tissue remodeling performance. In the current study, polymers and peptide were explored to develop scaffolds for wound healing and skin tissue regeneration. Alginate (Alg), chitosan (CS), and arginine-glycine-aspartate (RGD) were used to fabricate composite scaffolds crosslinked with tannic acid (TA), which also served as a bioactive. The use of RGD transformed the physicochemical and morphological features of the 3D scaffolds and TA crosslinking of the scaffolds improved their mechanical properties, specifically tensile strength, compressive Young's modulus, yield strength, and ultimate compressive strength. The incorporation of TA as both a crosslinker and a bioactive allowed for 86% encapsulation efficiency and burst release of 57% of TA in 24 h, accompanied by an 8.5% steady release per day of up to 90% over 5 d. The scaffolds increased mouse embryonic fibroblast cell viability over 3 d, progressing from slightly cytotoxic to non-cytotoxic (cell viability >90%). Wound closure and tissue regeneration evaluations in a SpragueDawley rat wound model at predetermined wound healing time points highlighted the superiority of the Alg-RGD-CS and Alg-RGD-CS-TA scaffolds over the commercial comparator product and control. The scaffolds' superior performance included accelerated tissue remodeling performance from the early to the late stages of wound healing, indicated by the lack of defects and scarring in scaffold-treated tissues. This promising performance supports the design of wound dressings that can act as delivery systems for the treatment of acute and chronic wounds.

In Situ Forming Chitosan-Alginate Interpolymer Complex Bioplatform for Wound Healing and Regeneration.

Cytocompatibility, biocompatibility, and biodegradability are amongst the most desirable qualities of wound dressings and can be tuned during the bioplatform fabrication steps to enhance wound healing capabilities. A three-stepped approach (partial-crosslinking, freeze-drying, and pulverisation) was employed in fabricating a particulate, partially crosslinked (PC), and transferulic acid (TFA)-loaded chitosan-alginate (CS-Alg) interpolymer complex (IPC) with enhanced wound healing capabilities. The PC TFA-CS-Alg IPC bioplatform displayed fluid uptake of 3102% in 24 h and a stepwise degradation up to 53.5% in 14 days. The PC TFA-CS-Alg bioplatform was used as a bioactive delivery system with an encapsulation efficiency of 65.6%, bioactive loading of 9.4%, burst release of 58.27%, and a steady release of 1.91% per day. PC TFA-CS-Alg displayed a shift in cytocompatibility from slightly cytotoxic (60-90% cell viability) to nontoxic (> 90% cell viability) over a 72-h period in NIH-3T3 cells. The wound closure and histological evaluations of the lesions indicated better wound healing performance in lesions treated with PC TFA-CS-Alg and PC CS-Alg compared to those treated with the commercial product and the control. Application of the particulate bioplatform on the wound via sprinkles, the in situ hydrogel formation under fluid exposure, and the accelerated wound healing performances of the bioplatforms make it a good candidate for bioactive delivery system and skin tissue regeneration.

Cell Secretome Strategies for Controlled Drug Delivery and Wound-Healing Applications.

There is significant interest in using stem cells in the management of cutaneous wounds. However, potential safety, efficacy, and cost problems associated with whole-cell transplantation hinder their clinical application. Secretome, a collective of mesenchymal stem-cell-stored paracrine factors, and immunomodulatory cytokines offer therapeutic potential as a cell-free therapy for the treatment of cutaneous wounds. This review explores the possibility of secretome as a treatment for cutaneous wounds and tissue regeneration. The review mainly focuses on in vitro and in vivo investigations that use biomaterials and secretome together to treat wounds, extend secretome retention, and control release to preserve their biological function. The approaches employed for the fabrication of biomaterials with condition media or extracellular vesicles are discussed to identify their future clinical application in wound treatment.

Bioplatform Fabrication Approaches Affecting Chitosan-Based Interpolymer Complex Properties and Performance as Wound Dressings.

Chitosan can form interpolymer complexes (IPCs) with anionic polymers to form biomedical platforms (BMPs) for wound dressing/healing applications. This has resulted in its application in various BMPs such as gauze, nano/microparticles, hydrogels, scaffolds, and films. Notably, wound healing has been highlighted as a noteworthy application due to the remarkable physical, chemical, and mechanical properties enabled though the interaction of these polyelectrolytes. The interaction of chitosan and anionic polymers can improve the properties and performance of BMPs. To this end, the approaches employed in fabricating wound dressings was evaluated for their effect on the property-performance factors contributing to BMP suitability in wound dressing. The use of chitosan in wound dressing applications has had much attention due to its compatible biological properties. Recent advancement includes the control of the degree of crosslinking and incorporation of bioactives in an attempt to enhance the physicochemical and physicomechanical properties of wound dressing BMPs. A critical issue with polyelectrolyte-based BMPs is that their effective translation to wound dressing platforms has yet to be realised due to the unmet challenges faced when mimicking the complex and dynamic wound environment. Novel BMPs stemming from the IPCs of chitosan are discussed in this review to offer new insight into the tailoring of physical, chemical, and mechanical properties via fabrication approaches to develop effective wound dressing candidates. These BMPs may pave the way to new therapeutic developments for improved patient outcomes.

Development of a fluid-absorptive alginate-chitosan bioplatform for potential application as a wound dressing.

This study introduces a novel approach in fabricating bioplatforms with favourable physical, chemical, and mechanical properties for wound dressing applications. The approach employs a three-step method; partial-crosslinking of polymers into soft macromatrices, lyophilization, and pulverization of those macromatrices to obtain polymer particles with improved properties. For investigation of this approach, the ionic polysaccharides, sodium alginate and chitosan were partially crosslinked with calcium chloride and sodium tripolyphosphate, respectively, followed by interpolymer complexation (IPC) for formation of the bioplatform. The formulations displayed good thermal stability with enhanced water uptake. The IPC exhibited water uptake of 4343.4% over 24 h and displayed 78% biodegradation over 14 days, which was superior to that of a commercial alginate-based wound dressing (1612.56% swelling and 16.26% biodegradation). The bioplatform thus possessed promising fluid-absorptivity and biodegradability, for potential application as a wound therapeutic system.