Advanced multi-targeted composite biomaterial dressing for pain and infection control in chronic leg ulcers

This study aimed to develop advanced biomaterial polysaccharide based dressings to manage pain associated with infected chronic leg ulcers in older adults. Composite carrageenan (CARR) and hyaluronic acid (HA) dressings loaded with lidocaine (LID) and AgNPs were formulated as freeze-dried wafers and functionally characterized for porous microstructure (morphology), mechanical strength, moisture handling properties, swelling, adhesion and lidocaine release. Antimicrobial activity of AgNPs was evaluated (turbidity assay) against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus whilst cell viability studies (MTT) was performed on normal adult human primary epidermal keratinocyte cells. The wafers were soft, flexible and elegant in appearance. HA affected the wafer structure by increasing the resistance to compression but still possessed a balance between toughness and flexibility to withstand normal stresses and prevent damage to newly formed skin tissue respectively. Water uptake was influenced by HA, whilst equilibrium water content and LID release were similar for all the formulations, showing controlled release up to 6 h. AgNPs loaded CARR/HA wafers were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. MTT assay showed evidence that the AgNPs/ LID loaded wafers did not interfere with cell viability and growth. CARR/HA wafers seem to be a promising system to simultaneously deliver LID and AgNPs, directly to infected chronic leg ulcers

Development of advanced analgesic dressings for chronic wound healing

Background: Pain is a ubiquitous problem in patients with chronic leg wounds. Recent studies have reported that 17 - 65% of patients experience severe or continuous pain that, associated with other characteristics of chronic ulcers such as odour, have debilitating effects on the patients including both their mental and psychological wellbeing. The aim of this work is to develop advanced wound dressings for local delivery of an analgesic drug that can help to manage pain associated with chronic leg ulcers in older adults. The addition of hyaluronic acid (HA) in the composition added beneficial and well recognized HA properties in the wound healing process. Methods: Advanced dressings loaded with an analgesic drug (lidocaine) were formulated as lyophilised xerogels (wafers) by freeze-drying. Different HA ratios by weight were used to improve the wafer characteristics. The dressings were tested for functional characteristics including mechanical strength, porous microstructure, stability, polymorphic/amorphous transitions, hydration, swelling and in vitro mucoadhesion. An HPLC method was developed to assess lidocaine release from wafers. Results: On the basis of feasibility study of the use of analgesic dressings in older adults with leg ulcers, an advanced dressing loaded with lidocaine was formulated. Wafers, due to their porous nature, have proved to be suitable for medium to high exuding wounds (common in leg ulcers), whilst still maintaining their physical integrity. Both blank and drug-loaded wafers were soft, flexible, elegant in appearance and non-brittle in nature. The addition of HA had an influence on wafer structure changing their properties, but mechanical characterisation demonstrated that the wafers were strong enough to withstand normal stresses but also flexible to prevent damage to newly formed skin tissue. The lidocaine release from the optimised dressing showed continuous release for over 12 h. Conclusions: Wafer seems to be a very promising system for delivery of analgesic drug to the wound. Further studies are in progress to evaluate in vitro activity of the dressings and role of HA in the wound healing process

3D-printed scaffold composites for the stimuli-induced local delivery of bioactive adjuncts

Polysaccharide scaffolds have been successfully employed to reconstruct environments that sustain skin tissue regeneration after injuries. Three-dimensional (3D) advanced additive manufacturing technologies allow creating scaffolds with controlled and reproducible macro- and micro-structure that improve the quality of the restored tissue to favor spontaneous repair. However, when persistent inflammation occurs, the physiological tissue healing capacity is reduced, like in the presence of pathologies like diabetes, vascular diseases, chronic infection, and others. In these circumstances, the bioavailability of therapeutic adjuncts like the growth factors in addition to the standard treatments represents undoubtedly a promising strategy to accelerate the healing of skin lesions. Precisely designed polysaccharide scaffolds obtained by 3D printing represent a robust platform that can be further implemented with the controlled delivery of bioactive adjuncts. Human elastin-like polypeptides (HELPs) are stimuli-responsive biopolymers. Their structure allows the integration of domains endowed with biological functionality, making them attractive compounds to prepare composites with smart properties. In the present study, 3D-printed alginate and chitosan scaffolds were combined with the HELP components. The HELP biopolymer was fused to the epidermal growth factor (EGF) as the bioactive domain. Different constructs were prepared and the stimuli-responsive behavior as well as the biological activity were evaluated, suggesting that these smart bioactive composites are suitable to realize multifunctional dressings that sustain the local release of therapeutic adjuncts

Alginate/human elastin-like polypeptide composite films with antioxidant properties for potential wound healing application

In this contribution we describe the preparation and characterization of a series of cross-linked films based on the combination of an elastin-derived biomimetic polypeptide (Human elastin-like polypeptide (HELP)) with alginate (ALG) to obtain a composite with enhanced properties. ALG/HELP composite films loaded with the hydrophobic natural antioxidant curcumin were prepared by solvent casting method followed by the cross-linking with calcium chloride. The compatibility between the two components as well as the final properties was evaluated. The micro-morphological study of films showed a homogeneous structure, but the film tensile strength decrease with HELP content and elongation at break was adversely affected by biopolymer addition. Spectroscopic and thermal analyses confirmed an interaction between ALG and HELP which also causes a modification in swelling kinetics and faster degradation. Moreover, the study of curcumin release showed a controlled delivery up to 10\u202fdays with a faster release rate in the presence of HELP. Human Dermal Fibroblasts (hDF) were used to test the in vitro cytocompatibility. The antioxidant activity correlated to the increase of HELP content suggested the applicability of these composites to develop smart biomaterials. Overall, these features indicated how this composite material has considerable potential as customizable platforms for various biomedical applications

Composite alginate-hyaluronan sponges for the delivery of tranexamic acid in post-extractive alveolar wounds

The management of wounds in patients on anticoagulant therapy who require oral surgical procedures is problematic and often results in a non-satisfactory healing process. Here we report a method to prepare an advanced dressing able to avoid uncontrolled bleeding by occluding the post-extractive alveolar wounds, and simultaneously, capable of a fast release of tranexamic acid (TA). Composite alginate/hyaluronan (ALG/HA) sponge dressings loaded with TA were prepared by a straightforward internal gelation method followed by a freeze-drying step. Both blank and drug-loaded sponges were soft, flexible, elegant in appearance and non-brittle in nature. SEM analysis confirmed the porous nature of these dressings. The integration of HA influenced the microstructure, reducing the porosity, modifying the water uptake kinetic and increasing the resistance to compression. TA release from ALG/HA sponges showed a controlled release up to 3h and it was faster in the presence of HA. Finally, an in vitro clotting test performed on human whole blood confirmed that the TA-loaded sponges significantly reduce the blood clotting index (BCI) by 30% compared to ALG/HA20 sponges. These results suggest that, if placed in a socket cavity, these dressings could give a relevant help to the blood hemostasis after dental extractions, especially in patients with coagulation disorders

Melt-spun bioactive sutures containing nanohybrids for local delivery of anti-inflammatory drugs.

In this work, a novel concept is introduced in drug-eluting fibres to ensure a good control of drug delivery features and wide applicability to different bioactive compounds. Composite bioactive sutures based on fibre grade poly(ε-caprolactone) (PCL) and loaded with the anti-inflammatory drug Diclofenac (Dic) or a Dic nanohybrid where the drug is intercalated in a synthetic hydrotalcite (Mg/Al hydroxycarbonate) (HT-Dic) were developed. Fibres were prepared by melt-spinning at different PCL/HT-Dic/Dic ratios and analysed in terms of morphology, mechanical properties and drug release features. Results emphasized that tensile properties of fibres are clearly affected by Dic or HT-Dic addition, while the presence of knots has limited influence on the mechanical behaviour of the sutures. Release of Dic strongly depends on how Dic is loaded in the fibre (as free or nanohybrid) whereas the combination of free Dic and HT-Dic can allow a further tuning of release profile. In vivo experiments show a reduction of inflammatory responses associated with Dic-loaded fibers. Thus, a proof of principle is provided for a novel class of bioactive sutures integrating advanced controlled-release technologies

Advanced therapeutic dressings for effective wound healing

Advanced therapeutic dressings that take active part in wound healing to achieve rapid and complete healing of chronic wounds is of current research interest. There is a desire for novel strategies to achieve expeditious wound healing due to the enormous financial burden worldwide. This paper reviews the current state of wound healing and wound management products, with emphasis on the demand for more advanced forms of wound therapy and some of the current challenges and driving forces behind this demand. The paper reviews information mainly from peer reviewed literature and other publicly available sources such as the FDA. A major focus is the treatment of chronic wounds including amputations, diabetic and leg ulcers, pressure sores, surgical and traumatic wounds (e.g. accidents and burns) where patient immunity is low and the risk of infections and complications are high. The main dressings include medicated moist dressings, tissue engineered substitutes, biomaterials based biological dressings, biological and naturally derived dressings, medicated sutures and various combinations of the above classes. Finally, the review briefly discusses possible prospects of advanced wound healing including some of the emerging approaches such as hyperbaric oxygen, negative pressure wound therapy and laser wound healing, in routine clinical care

HELPING WOUND HEALING PROCESS THROUGH DRUG DELIVERY SISTEMS

Wound repair is a complex and coordinated process that involves the participation of all the principal molecular and biochemical processes involved in growth and cell differentiation. The in situ administration of bioactive molecules through drug delivery systems can result in enormous therapeutic benefits as it would increase the concentration of the active drugs in the site of interest in time, minimizing the systemic action. In case of both acute and chronic wounds, a local delivery permits a more rapid wound healing with reduced complications due to infection or other diseases. Based on these considerations, the purpose of this thesis is the development of innovative polymer-based delivery systems capable to exert a direct action on wound healing promoting a rapid recovery of tissue function. In the first three chapters alginate-based hydrogels useful for wound treatment in form of hydrated and spongy-like sheets, have been successfully developed. Using different gelation techniques, silver nanoparticles and tea tree oil nanoemulsions were loaded in the alginate hydrogel to obtain a bioactivatedl device with a direct action on wound healing process. Finally, hybrid synthetic hydrotalcite particles loaded with an anti-inflammatory drug were integrated in biodegradable fibers with the aim to achieve bioactive sutures