Chitosan-Based Biomaterials for Tissue Regeneration.

Chitosan is a chitin-derived biopolymer that has shown great potential for tissue regeneration and controlled drug delivery. It has numerous qualities that make it attractive for biomedical applications such as biocompatibility, low toxicity, broad-spectrum antimicrobial activity, and many others. Importantly, chitosan can be fabricated into a variety of structures including nanoparticles, scaffolds, hydrogels, and membranes, which can be tailored to deliver a desirable outcome. Composite chitosan-based biomaterials have been demonstrated to stimulate in vivo regeneration and the repair of various tissues and organs, including but not limited to, bone, cartilage, dental, skin, nerve, cardiac, and other tissues. Specifically, de novo tissue formation, resident stem cell differentiation, and extracellular matrix reconstruction were observed in multiple preclinical models of different tissue injuries upon treatment with chitosan-based formulations. Moreover, chitosan structures have been proven to be efficient carriers for medications, genes, and bioactive compounds since they can maintain the sustained release of these therapeutics. In this review, we discuss the most recently published applications of chitosan-based biomaterials for different tissue and organ regeneration as well as the delivery of various therapeutics.

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction.

Cardiac fibrosis is a common pathological consequence of most myocardial diseases. It is associated with the excessive accumulation of extracellular matrix proteins as well as fibroblast differentiation into myofibroblasts in the cardiac interstitium. This structural remodeling often results in myocardial dysfunctions such as arrhythmias and impaired systolic function in patients with heart conditions, ultimately leading to heart failure and death. An understanding of the precise mechanisms of cardiac fibrosis is still limited due to the numerous signaling pathways, cells, and mediators involved in the process. This review article will focus on the pathophysiological processes associated with the development of cardiac fibrosis. In addition, it will summarize the novel strategies for anti-fibrotic therapies such as epigenetic modifications, miRNAs, and CRISPR technologies as well as various medications in cellular and animal models.

Stimuli-Responsive Polymers for Transdermal, Transmucosal and Ocular Drug Delivery.

Despite their conventional and widespread use, oral and intravenous routes of drug administration face several limitations. In particular, orally administered drugs undergo enzymatic degradation in the gastrointestinal tract and first-pass metabolism in the liver, which tend to decrease their bioavailability. Intravenous infusions of medications are invasive, painful and stressful for patients and carry the risk of infections, tissue damage and other adverse reactions. In order to account for these disadvantages, alternative routes of drug delivery, such as transdermal, nasal, oromucosal, ocular and others, have been considered. Moreover, drug formulations have been modified in order to improve their storage stability, solubility, absorption and safety. Recently, stimuli-responsive polymers have been shown to achieve controlled release and enhance the bioavailability of multiple drugs. In this review, we discuss the most up-to-date use of stimuli-responsive materials in order to optimize the delivery of medications that are unstable to pH or undergo primary metabolism via transdermal, nasal, oromucosal and ocular routes. Release kinetics, diffusion parameters and permeation rate of the drug via the mucosa or skin are discussed as well.

Peptide-Based Drug Delivery Systems.

Peptide-based drug delivery systems have many advantages when compared to synthetic systems in that they have better biocompatibility, biochemical and biophysical properties, lack of toxicity, controlled molecular weight via solid phase synthesis and purification. Lysosomes, solid lipid nanoparticles, dendrimers, polymeric micelles can be applied by intravenous administration, however they are of artificial nature and thus may induce side effects and possess lack of ability to penetrate the blood-brain barrier. An analysis of nontoxic drug delivery systems and an establishment of prospective trends in the development of drug delivery systems was needed. This review paper summarizes data, mainly from the past 5 years, devoted to the use of peptide-based carriers for delivery of various toxic drugs, mostly anticancer or drugs with limiting bioavailability. Peptide-based drug delivery platforms are utilized as peptide-drug conjugates, injectable biodegradable particles and depots for delivering small molecule pharmaceutical substances (500 Da) and therapeutic proteins. Controlled drug delivery systems that can effectively deliver anticancer and peptide-based drugs leading to accelerated recovery without significant side effects are discussed. Moreover, cell penetrating peptides and their molecular mechanisms as targeting peptides, as well as stimuli responsive (enzyme-responsive and pH-responsive) peptides and peptide-based self-assembly scaffolds are also reviewed.

Recent Advances in Gene Therapy for Cardiac Tissue Regeneration.

Cardiovascular diseases (CVDs) are responsible for enormous socio-economic impact and the highest mortality globally. The standard of care for CVDs, which includes medications and surgical interventions, in most cases, can delay but not prevent the progression of disease. Gene therapy has been considered as a potential therapy to improve the outcomes of CVDs as it targets the molecular mechanisms implicated in heart failure. Cardiac reprogramming, therapeutic angiogenesis using growth factors, antioxidant, and anti-apoptotic therapies are the modalities of cardiac gene therapy that have led to promising results in preclinical studies. Despite the benefits observed in animal studies, the attempts to translate them to humans have been inconsistent so far. Low concentration of the gene product at the target site, incomplete understanding of the molecular pathways of the disease, selected gene delivery method, difference between animal models and humans among others are probable causes of the inconsistent results in clinics. In this review, we discuss the most recent applications of the aforementioned gene therapy strategies to improve cardiac tissue regeneration in preclinical and clinical studies as well as the challenges associated with them. In addition, we consider ongoing gene therapy clinical trials focused on cardiac regeneration in CVDs.

Immunology of Acute and Chronic Wound Healing.

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1ß, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.

Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction.

Cardiovascular disease is the leading cause of mortality and morbidity around the globe, creating a substantial socio-economic burden as a result. Myocardial infarction is a significant contributor to the detrimental impact of cardiovascular disease. The death of cardiomyocytes following myocardial infarction causes an immune response which leads to further destruction of tissue, and subsequently, results in the formation of non-contractile scar tissue. Macrophages have been recognized as important regulators and participants of inflammation and fibrosis following myocardial infarction. Macrophages are generally classified into two distinct groups, namely, classically activated, or M1 macrophages, and alternatively activated, or M2 macrophages. The phenotypic profile of cardiac macrophages, however, is much more diverse and should not be reduced to these two subsets. In this review, we describe the phenotypes and functions of macrophages which are present in the healthy, as well as the infarcted heart, and analyze them with respect to M1 and M2 polarization states. Furthermore, we discuss therapeutic strategies which utilize macrophage polarization towards an anti-inflammatory or reparative phenotype for the treatment of myocardial infarction.

Progress and Prospects of Polymer-Based Drug Delivery Systems for Bone Tissue Regeneration.

Despite the high regenerative capacity of bone tissue, there are some cases where bone repair is insufficient for a complete functional and structural recovery after damage. Current surgical techniques utilize natural and synthetic bone grafts for bone healing, as well as collagen sponges loaded with drugs. However, there are certain disadvantages associated with these techniques in clinical usage. To improve the therapeutic efficacy of bone tissue regeneration, a number of drug delivery systems based on biodegradable natural and synthetic polymers were developed and examined in in vitro and in vivo studies. Recent studies have demonstrated that biodegradable polymers play a key role in the development of innovative drug delivery systems and tissue engineered constructs, which improve the treatment and regeneration of damaged bone tissue. In this review, we discuss the most recent advances in the field of polymer-based drug delivery systems for the promotion of bone tissue regeneration and the physical-chemical modifications of polymers for controlled and sustained release of one or more drugs. In addition, special attention is given to recent developments on polymer nano- and microparticle-based drug delivery systems for bone regeneration.