The evolving field of regenerative aesthetics.

BACKGROUND: Regenerative aesthetics (RA) is an emerging subfield based on many of the principles of regenerative medicine (RM). In order to ensure that the development of regenerative aesthetics is based on accepted regenerative concepts and to optimize treatment strategies, it is important to establish clear definitions, fundamental aims and consider the impact of the predominant RA tissue environment RM focuses on the regeneration of injured or diseased tissue, while RA aims to restore youthful properties to aging, senescent tissue. The distinction is key in understanding how best to develop treatments for these different goals. AIMS AND METHODS: The current review suggests key concepts, definitions, and foundations of regenerative aesthetic approaches and examines current evidence supporting this. It considers the importance of the aging tissue environment, the essential regenerative goals of restored tissue structure and function and introduces the concept of regenerative scaffolds with a focus on CaHA. Current techniques in the field and promising future directions are also discussed. CONCLUSION: Regenerative aesthetics is an evolving subfield of regenerative medicine. Establishing clear definitions, identifying the challenges of the aging soft tissue environment and re-evaluating current evidence in light of regenerative goals are vital for the continuing evolution of this medical field.

Tendon tissue engineering: Current progress towards an optimized tenogenic differentiation protocol for human stem cells.

Tendons are integral to our daily lives by allowing movement and locomotion but are frequently injured, leading to patient discomfort and impaired mobility. Current clinical procedures are unable to fully restore the native structure of the tendon, resulting in loss of full functionality, and the weakened tissue following repair often re-ruptures. Tendon tissue engineering, involving the combination of cells with biomaterial scaffolds to form new tendon tissue, holds promise to improve patient outcomes. A key requirement for efficacy in promoting tendon tissue formation is the optimal differentiation of the starting cell populations, most commonly adult tissue-derived mesenchymal stem/stromal cells (MSCs), into tenocytes, the predominant cellular component of tendon tissue. Currently, a lack of consensus on the protocols for effective tenogenic differentiation is hampering progress in tendon tissue engineering. In this review, we discuss the current state of knowledge regarding human stem cell differentiation towards tenocytes and tendon tissue formation. Tendon development and healing mechanisms are described, followed by a comprehensive overview of the current protocols for tenogenic differentiation, including the effects of biochemical and biophysical cues, and their combination, on tenogenesis. Lastly, a synthesis of the key features of these protocols is used to design future approaches. The holistic evaluation of current knowledge should facilitate and expedite the development of efficacious stem cell tenogenic differentiation protocols with future impact in tendon tissue engineering. STATEMENT OF SIGNIFICANCE: The lack of a widely-adopted tenogenic differentiation protocol has been a major hurdle in the tendon tissue engineering field. Building on current knowledge on tendon development and tendon healing, this review surveys peer-reviewed protocols to present a holistic evaluation and propose a pathway to facilitate and expedite the development of a consensus protocol for stem cell tenogenic differentiation and tendon tissue engineering.

Innovative Biological Treatment Methods for Degenerative Disc Disease.

Low back pain is the leading cause of work absences and years lived with disability, and it is often associated with degenerative disc disease. In recent years, biological treatment approaches such as the use of growth factors, cell injections, annulus fibrosus (AF) repair, nucleus pulposus replacement, and tissue-engineered discs have been explored as means for preventing or reversing degenerative disc disease. Both animal and clinical studies have shown promising results for cell-based therapy on the grounds of its regenerative potential. Clinical data also indicate that stem cell injection is safe when appropriately performed, albeit its long-term safety and efficacy are yet to be explored. Numerous challenges also remain to be overcome, such as isolating, differentiating, and preconditioning the disc cells, as well as managing the nutrient-deficient and oxygen-deficient micromilieu of the intervertebral disc (IVD). AF repair methods including devices used in clinical trials have shown success in decreasing reherniation rates and improving overall clinical outcomes. In addition, recent studies that combined AF repair and nucleus pulposus replacement have shown improved biomechanical stability in IVDs after the combined treatment. Tissue-engineered IVDs for total disc replacement are still being developed, and future studies are necessary to overcome the challenges in their delivery, efficacy, and safety.

Collagen-based formulations for wound healing: A literature review.

Wounds have always been the point of concern owing to the involvement of infections and the level of severity. Therefore, the management of wounds always requires additional effort for comprehensive healing and subsequent removal of the scar from the wound site. The role of biomaterials in the management of chronic wounds has been well established. One of such biomaterials is collagen (Col) that is considered to be the crucial component of most of the formulations being developed for wound healing. The role of Col extracted from marine invertebrates remains an unmarked origin of the proteinaceous constituent in the evolution of innovative pharmaceuticals. Col is a promising, immiscible, fibrous amino acid of indigenous origin that is ubiquitously present in extracellular matrices and connective tissues. There are different types of Col present in the body such as type I, II, III, IV, and V however the natural sources of Col are vegetables and marine animals. Its physical properties like high tensile strength, adherence nature, elasticity, and remodeling contribute significantly in the wound healing process. Col containing formulations such as hydrogels, sponges, creams, peptides, and composite nanofibers have been utilized widely in wound healing and tissue engineering purposes truly as the first line of defense. Here we present the recent advancements in Col based dosage forms for wound healing. The Col based market of topical preparations and the published reports identify Colas a useful biomaterial for the delivery of pharmaceuticals and a platform for tissue engineering.

When cells become medicines: A South African perspective.

The discovery of human leucocyte antigen (HLA), serological matching and HLA-typing techniques, combined with the development of immunosuppressive medicines and improvements in infection control, have opened the way to cell, tissue and vascularised organ transplantation. Since the early 1960s, more than a million haematopoietic progenitor cell (HPC) transplantations have been performed worldwide to restore haematopoiesis and support immune system recovery after bone marrow ablation. HPC transplantation uses minimally manipulated autologous or allogeneic cells to restore the homologous functions of bone marrow. Research in biological sciences supported by new technologies is increasingly translated into therapeutic products intended to augment, repair, replace or regenerate genes, cells, tissues, organs and metabolic processes in the body. These products are referred to as regenerative medicine therapies or advanced therapy medicinal products, and include gene therapies, cell-based therapies and engineered tissue products.

Conductive Polymeric-Based Electroactive Scaffolds for Tissue Engineering Applications: Current Progress and Challenges from Biomaterials and Manufacturing Perspectives.

The practice of combining external stimulation therapy alongside stimuli-responsive bio-scaffolds has shown massive potential for tissue engineering applications. One promising example is the combination of electrical stimulation (ES) and electroactive scaffolds because ES could enhance cell adhesion and proliferation as well as modulating cellular specialization. Even though electroactive scaffolds have the potential to revolutionize the field of tissue engineering due to their ability to distribute ES directly to the target tissues, the development of effective electroactive scaffolds with specific properties remains a major issue in their practical uses. Conductive polymers (CPs) offer ease of modification that allows for tailoring the scaffold's various properties, making them an attractive option for conductive component in electroactive scaffolds. This review provides an up-to-date narrative of the progress of CPs-based electroactive scaffolds and the challenge of their use in various tissue engineering applications from biomaterials perspectives. The general issues with CP-based scaffolds relevant to its application as electroactive scaffolds were discussed, followed by a more specific discussion in their applications for specific tissues, including bone, nerve, skin, skeletal muscle and cardiac muscle scaffolds. Furthermore, this review also highlighted the importance of the manufacturing process relative to the scaffold's performance, with particular emphasis on additive manufacturing, and various strategies to overcome the CPs' limitations in the development of electroactive scaffolds.

Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering.

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic ß-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost ß-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring ß-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived ß-like cells to restore ß-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of ß-cell replacement therapies.

Engineering islets from stem cells for advanced therapies of diabetes.

Diabetes mellitus is a metabolic disorder that affects more than 460 million people worldwide. Type 1 diabetes (T1D) is caused by autoimmune destruction of ß-cells, whereas type 2 diabetes (T2D) is caused by a hostile metabolic environment that leads to ß-cell exhaustion and dysfunction. Currently, first-line medications treat the symptomatic insulin resistance and hyperglycaemia, but do not prevent the progressive decline of ß-cell mass and function. Thus, advanced therapies need to be developed that either protect or regenerate endogenous ß-cell mass early in disease progression or replace lost ß-cells with stem cell-derived ß-like cells or engineered islet-like clusters. In this Review, we discuss the state of the art of stem cell differentiation and islet engineering, reflect on current and future challenges in the area and highlight the potential for cell replacement therapies, disease modelling and drug development using these cells. These efforts in stem cell and regenerative medicine will lay the foundations for future biomedical breakthroughs and potentially curative treatments for diabetes.

Amino acid derived biopolymers: Recent advances and biomedical applications.

Over the past few years, amino acids (AA) have emerged as promising biomaterials for the synthesis of functional polymers. Owing to the diversity of functional groups in amino acids, various polymerization methods may be used to make a wide range of well-defined functional amino-acid/peptide-based optically active polymers with varying polymer lengths, compositions, and designs. When incorporated with chirality and self-assembly, they offer a wide range of applications and are particularly appealing in the field of drug delivery, tissue engineering, and biosensing. There are several classes of these polymers that include polyamides (PA), polyesters (PE), poly(ester-amide)s (PEA)s, polyurethanes (PU)s, poly(depsipeptide)s (PDP)s, etc. They offer the ability to control functionality, conjugation, crosslinking, stimuli responsiveness, and tuneable mechanical/thermal properties. In this review, we present the recent advancements in the synthesis strategies for obtaining these amino acid-derived bio-macromolecules, their self-assembly properties, and the wealth of prevalent applications.

Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions.

Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren's syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor ß receptor (TGFßR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.

Biomimetic reduced graphene oxide coated collagen scaffold for in situ bone regeneration.

A variety of bone-related diseases and injures and limitations of traditional regeneration methods require new tissue substitutes. Tissue engineering and regeneration combined with nanomedicine can provide different natural or synthetic and combined scaffolds with bone mimicking properties for implantation in the injured area. In this study, we synthesized collagen (Col) and reduced graphene oxide coated collagen (Col-rGO) scaffolds, and we evaluated their in vitro and in vivo effects on bone tissue repair. Col and Col-rGO scaffolds were synthesized by chemical crosslinking and freeze-drying methods. The surface topography, and the mechanical and chemical properties of scaffolds were characterized, showing three-dimensional (3D) porous scaffolds and successful coating of rGO on Col. The rGO coating enhanced the mechanical strength of Col-rGO scaffolds to a greater extent than Col scaffolds by 2.8 times. Furthermore, Col-rGO scaffolds confirmed that graphene addition induced no cytotoxic effects and enhanced the viability and proliferation of human bone marrow-derived mesenchymal stem cells (hBMSCs) with 3D adherence and expansion. Finally, scaffold implantation into rabbit cranial bone defects for 12 weeks showed increased bone formation, confirmed by Hematoxylin-Eosin (H&E) and alizarin red staining. Overall, the study showed that rGO coating improves Col scaffold properties and could be a promising implant for bone injuries.

3D printed double-network alginate hydrogels containing polyphosphate for bioenergetics and bone regeneration.

Low mechanical strength, poor processability, and low bioactivity of hydrogels limit their application in bone tissue engineering severely. Herein, a new 3D-printable, osteoinductive, and bioenergetic-active double-network (DN) hydrogel containing sodium alginate (SA), poly (ethylene glycol) diacrylate (PEGDA), and sodium polyphosphate (PolyP) was developed via a two-step method. The synergy of the covalent cross-linking network and the ionic cross-linking network improves the mechanical properties of the hydrogel. And the pre-gel with Ca2+ has better 3D printing performance to print complex tissue engineering scaffolds than common hydrogels. In addition, the incorporation of PolyP into DN hydrogel matrix significantly improves the bioactivity of hydrogels. The bioenergetic effect of PolyP improves adenosine triphosphate content of cells significantly to promote cell activities such as migration. The in vitro osseointegration investigation suggests that the orthophosphate monomer units, which are degradation fragments of PolyP, provide enough phosphoric acid units for the formation of calcium phosphate and accelerate the osteogenic differentiation of cells greatly. Therefore, the proposed printable, bioenergetic-active, osteoinductive DN hydrogel is potential to solve the problems of complex tissue engineering scaffolds and be applied in energy-crucial bone tissue regeneration.

PGS/HAp Microporous Composite Scaffold Obtained in the TIPS-TCL-SL Method: An Innovation for Bone Tissue Engineering.

In this research, we synthesize and characterize poly(glycerol sebacate) pre-polymer (pPGS) (1H NMR, FTiR, GPC, and TGA). Nano-hydroxyapatite (HAp) is synthesized using the wet precipitation method. Next, the materials are used to prepare a PGS-based composite with a 25 wt.% addition of HAp. Microporous composites are formed by means of thermally induced phase separation (TIPS) followed by thermal cross-linking (TCL) and salt leaching (SL). The manufactured microporous materials (PGS and PGS/HAp) are then subjected to imaging by means of SEM and µCT for the porous structure characterization. DSC, TGA, and water contact angle measurements are used for further evaluation of the materials. To assess the cytocompatibility and biological potential of PGS-based composites, preosteoblasts and differentiated hFOB 1.19 osteoblasts are employed as in vitro models. Apart from the cytocompatibility, the scaffolds supported cell adhesion and were readily populated by the hFOB1.19 preosteoblasts. HAp-facilitated scaffolds displayed osteoconductive properties, supporting the terminal differentiation of osteoblasts as indicated by the production of alkaline phosphatase, osteocalcin and osteopontin. Notably, the PGS/HAp scaffolds induced the production of significant amounts of osteoclastogenic cytokines: IL-1ß, IL-6 and TNF-α, which induced scaffold remodeling and promoted the reconstruction of bone tissue. Initial biocompatibility tests showed no signs of adverse effects of PGS-based scaffolds toward adult BALB/c mice.

Recent advances in regenerative medicine strategies for cancer treatment.

Cancer stands as one of the most leading causes of death worldwide, while one of the most significant challenges in treating it is revealing novel alternatives to predict, diagnose, and eradicate tumor cell growth. Although various methods, such as surgery, chemotherapy, and radiation therapy, are used today to treat cancer, its mortality rate is still high due to the numerous shortcomings of each approach. Regenerative medicine field, including tissue engineering, cell therapy, gene therapy, participate in cancer treatment and development of cancer models to improve the understanding of cancer biology. The final intention is to convey fundamental and laboratory research to effective clinical treatments, from the bench to the bedside. Proper interpretation of research attempts helps to lessen the burden of treatment and illness for patients. The purpose of this review is to investigate the role of regenerative medicine in accelerating and improving cancer treatment. This study examines the capabilities of regenerative medicine in providing novel cancer treatments and the effectiveness of these treatments to clarify this path as much as possible and promote advanced future research in this field.

Can Human Oral Mucosa Stem Cells Differentiate to Corneal Epithelia?

Human oral mucosa stem cells (hOMSCs) arise from the neural crest, they can self-renew, proliferate, and differentiate to several cell lines and could represent a good source for application in tissue engineering. Because of their anatomical location, hOMSCs are easy to isolate, have multilineage differentiation capacity and express embryonic stem cells markers such as-Sox2, Oct3/4 and Nanog. We have used SHEM (supplemented hormonal epithelial medium) media and cultured hOMSCs over human amniotic membrane and determined the cell's capacity to differentiate to an epithelial-like phenotype and to express corneal specific epithelial markers-CK3, CK12, CK19, Pan-cadherin and E-cadherin. Our results showed that hOMSCs possess the capacity to attach to the amniotic membrane and express CK3, CK19, Pan-Cadherin and E-Cadherin without induction with SHEM media and expressed CK12 or changed the expression pattern of E-Cadherin to a punctual-like feature when treated with SHEM media. The results observed in this study show that hOMSCs possess the potential to differentiate toward epithelial cells. In conclusion, our results revealed that hOMSCs readily express markers for corneal determination and could provide the ophthalmology field with a therapeutic alternative for tissue engineering to achieve corneal replacement when compared with other techniques. Nevertheless, further studies are needed to develop a predictable therapeutic alternative for cornea replacement.

Advances in tissue engineering of vasculature through three-dimensional bioprinting.

BACKGROUND: A significant challenge facing tissue engineering is the fabrication of vasculature constructs which contains vascularized tissue constructs to recapitulate viable, complex and functional organs or tissues, and free-standing vascular structures potentially providing clinical applications in the future. Three-dimensional (3D) bioprinting has emerged as a promising technology, possessing a number of merits that other conventional biofabrication methods do not have. Over the last decade, 3D bioprinting has contributed a variety of techniques and strategies to generate both vascularized tissue constructs and free-standing vascular structures. RESULTS: This review focuses on different strategies to print two kinds of vasculature constructs, namely vascularized tissue constructs and vessel-like tubular structures, highlighting the feasibility and shortcoming of the current methods for vasculature constructs fabrication. Generally, both direct printing and indirect printing can be employed in vascularized tissue engineering. Direct printing allows for structural fabrication with synchronous cell seeding, while indirect printing is more effective in generating complex architecture. During the fabrication process, 3D bioprinting techniques including extrusion bioprinting, inkjet bioprinting and light-assisted bioprinting should be selectively implemented to exert advantages and obtain the desirable tissue structure. Also, appropriate cells and biomaterials matter a lot to match various bioprinting techniques and thus achieve successful fabrication of specific vasculature constructs. CONCLUSION: The 3D bioprinting has been developed to help provide various fabrication techniques, devoting to producing structurally stable, physiologically relevant, and biologically appealing constructs. However, although the optimization of biomaterials and innovation of printing strategies may improve the fabricated vessel-like structures, 3D bioprinting is still in the infant period and has a great gap between in vitro trials and in vivo applications. The article reviews the present achievement of 3D bioprinting in generating vasculature constructs and also provides perspectives on future directions of advanced vasculature constructs fabrication.

Application of 3D bioprinting in the prevention and the therapy for human diseases.

Rapid development of vaccines and therapeutics is necessary to tackle the emergence of new pathogens and infectious diseases. To speed up the drug discovery process, the conventional development pipeline can be retooled by introducing advanced in vitro models as alternatives to conventional infectious disease models and by employing advanced technology for the production of medicine and cell/drug delivery systems. In this regard, layer-by-layer construction with a 3D bioprinting system or other technologies provides a beneficial method for developing highly biomimetic and reliable in vitro models for infectious disease research. In addition, the high flexibility and versatility of 3D bioprinting offer advantages in the effective production of vaccines, therapeutics, and relevant delivery systems. Herein, we discuss the potential of 3D bioprinting technologies for the control of infectious diseases. We also suggest that 3D bioprinting in infectious disease research and drug development could be a significant platform technology for the rapid and automated production of tissue/organ models and medicines in the near future.

Recent trends in natural polysaccharide based bioinks for multiscale 3D printing in tissue regeneration: A review.

Biofabrication by three-dimensional (3D) printing has been an attractive technology in harnessing the possibility to print anatomical shaped native tissues with controlled architecture and resolution. 3D printing offers the possibility to reproduce complex microarchitecture of native tissues by printing live cells in a layer by layer deposition to provide a biomimetic structural environment for tissue formation and host tissue integration. Plant based biomaterials derived from green and sustainable sources have represented to emulate native physicochemical and biological cues in order to direct specific cellular response and formation of new tissues through biomolecular recognition patterns. This comprehensive review aims to analyze and identify the most commonly used plant based bioinks for 3D printing applications. An overview on the role of different plant based biomaterial of terrestrial origin (Starch, Nanocellulose and Pectin) and marine origin (Ulvan, Alginate, Fucoidan, Agarose and Carrageenan) used for 3D printing applications are discussed elaborately. Furthermore, this review will also emphasis in the functional aspects of different 3D printers, appropriate printing material, merits and demerits of numerous plant based bioinks in developing 3D printed tissue-like constructs. Additionally, the underlying potential benefits, limitations and future perspectives of plant based bioinks for tissue engineering (TE) applications are also discussed.