Hydrogels in Cutaneous Wound Healing: Insights into Characterization, Properties, Formulation and Therapeutic Potential.

Hydrogels are polymeric materials that possess a set of characteristics meeting various requirements of an ideal wound dressing, making them promising for wound care. These features include, among others, the ability to absorb and retain large amounts of water and the capacity to closely mimic native structures, such as the extracellular matrix, facilitating various cellular processes like proliferation and differentiation. The polymers used in hydrogel formulations exhibit a broad spectrum of properties, allowing them to be classified into two main categories: natural polymers like collagen and chitosan, and synthetic polymers such as polyurethane and polyethylene glycol. This review offers a comprehensive overview and critical analysis of the key polymers that can constitute hydrogels, beginning with a brief contextualization of the polymers. It delves into their function, origin, and chemical structure, highlighting key sources of extraction and obtaining. Additionally, this review encompasses the main intrinsic properties of these polymers and their roles in the wound healing process, accompanied, whenever available, by explanations of the underlying mechanisms of action. It also addresses limitations and describes some studies on the effectiveness of isolated polymers in promoting skin regeneration and wound healing. Subsequently, we briefly discuss some application strategies of hydrogels derived from their intrinsic potential to promote the wound healing process. This can be achieved due to their role in the stimulation of angiogenesis, for example, or through the incorporation of substances like growth factors or drugs, such as antimicrobials, imparting new properties to the hydrogels. In addition to substance incorporation, the potential of hydrogels is also related to their ability to serve as a three-dimensional matrix for cell culture, whether it involves loading cells into the hydrogel or recruiting cells to the wound site, where they proliferate on the scaffold to form new tissue. The latter strategy presupposes the incorporation of biosensors into the hydrogel for real-time monitoring of wound conditions, such as temperature and pH. Future prospects are then ultimately addressed. As far as we are aware, this manuscript represents the first comprehensive approach that brings together and critically analyzes fundamental aspects of both natural and synthetic polymers constituting hydrogels in the context of cutaneous wound healing. It will serve as a foundational point for future studies, aiming to contribute to the development of an effective and environmentally friendly dressing for wounds.

An Overview of Biosimilars-Development, Quality, Regulatory Issues, and Management in Healthcare.

Biological therapies have transformed high-burden treatments. As the patent and exclusivity period for biological medicines draws to a close, there is a possibility for the development and authorization of biosimilars. These products boast comparable levels of safety, quality, and effectiveness to their precursor reference products. Biosimilars, although similar to reference products, are not identical copies and should not be considered generic substitutes for the original. Their development and evaluation involve a rigorous step-by-step process that includes analytical, functional, and nonclinical evaluations and clinical trials. Clinical studies conducted for biosimilars aim to establish similar efficacy, safety, and immunogenicity, rather than demonstrating a clinical benefit, as with the reference product. However, although the current knowledge regarding biosimilars has significantly increased, several controversies and misconceptions still exist regarding their immunogenicity, extrapolation, interchangeability, substitution, and nomenclature. The development of biosimilars stimulates market competition, contributes toward healthcare sustainability, and allows for greater patient access. However, maximizing the benefits of biosimilars requires cooperation between regulators and developers to ensure that patients can benefit quickly from access to these new therapeutic alternatives while maintaining high standards of quality, safety, and efficacy. Recognizing the inherent complexities of comprehending biosimilars fully, it is essential to focus on realistic approaches, such as fostering open communication between healthcare providers and patients, encouraging informed decision-making, and minimizing risks. This review addresses the regulatory and manufacturing requirements for biosimilars and provides clinicians with relevant insights for informed prescribing.

Beyond the adverse effects of the systemic route: Exploiting nanocarriers for the topical treatment of skin cancers.

Skin cancer is a heterogeneous disease that can be divided into two main groups, melanoma and nonmelanoma skin cancers. Conventional therapies for skin cancer have numerous systemic side effects and a high recurrence rate. Topical treatment is an alternative approach, but drug permeability remains a challenge. Therefore, nanocarriers appear as important nanotechnology tools that reduces both the side effects and improves clinical outcomes. This is why they are attracting growing interest. In this review, scientific articles on the use of nanocarriers for the topical treatment of skin cancer were collected. Despite the promising results of the presented nanocarriers and considering that some of them are already on the market, there is an urgent need for investment in the development of manufacturing methods, as well as of suitable toxicological and regulatory evaluations, since the conventional methods currently used to develop these nanocarriers-based products are more time-consuming and expensive than conventional products.

Exploiting Pharma 4.0 Technologies in the Non-Biological Complex Drugs Manufacturing: Innovations and Implications.

The pharmaceutical industry has entered an era of transformation with the emergence of Pharma 4.0, which leverages cutting-edge technologies in manufacturing processes. These hold tremendous potential for enhancing the overall efficiency, safety, and quality of non-biological complex drugs (NBCDs), a category of pharmaceutical products that pose unique challenges due to their intricate composition and complex manufacturing requirements. This review attempts to provide insight into the application of select Pharma 4.0 technologies, namely machine learning, in silico modeling, and 3D printing, in the manufacturing process of NBCDs. Specifically, it reviews the impact of these tools on NBCDs such as liposomes, polymeric micelles, glatiramer acetate, iron carbohydrate complexes, and nanocrystals. It also addresses regulatory challenges associated with the implementation of these technologies and presents potential future perspectives, highlighting the incorporation of digital twins in this field of research as it seems to be a very promising approach, namely for the optimization of NBCDs manufacturing processes.

Inorganic nanoparticles in dermopharmaceutical and cosmetic products: Properties, formulation development, toxicity, and regulatory issues.

The use of nanotechnology strategies is a current hot topic, and research in this field has been growing significantly in the cosmetics industry. Inorganic nanoparticles stand out in this context for their distinctive physicochemical properties, leading in particular to an increased refractive index and absorption capacity giving them a broad potential for cutaneous applications and making them of special interest in research for dermopharmaceutical and cosmetic purposes. This performance is responsible for its heavy inclusion in the manufacture of skin health products such as sunscreens, lotions, beauty creams, skin ointments, makeup, and others. In particular, their suitable bandgap energy characteristics allow them to be used as photocatalytic semiconductors. They provide excellent UV absorption, commonly known as UV filters, and are responsible for their wide worldwide use in sunscreen formulations without the undesirable white residue after consumer application. In addition, cosmetics based on inorganic nanoparticles have several additional characteristics relevant to formulation development, such as being less expensive compared to other nanomaterials, having greater stability, and ensuring less irritation, itching, and propensity for skin allergies. This review will address in detail the main inorganic nanoparticles used in dermopharmaceutical and cosmetic products, such as titanium dioxide, zinc oxide, silicon dioxide, silver, gold, copper, and aluminum nanoparticles, nanocrystals, and quantum dots, reporting their physicochemical characteristics, but also their additional intrinsic properties that contribute to their use in this type of formulations. Safety issues regarding inorganic nanoparticles, based on toxicity studies, both to humans and the environment, as well as regulatory affairs associated with their use in dermopharmaceuticals and cosmetics, will be addressed.

Impact of GAMP 5, data integrity and QbD on quality assurance in the pharmaceutical industry: How obvious is it?

In the pharmaceutical industry, it is essential to ensure the safety and efficacy of medicinal products. Therefore a robust quality assurance framework is needed. This manuscript examines the impact of GAMP 5 and data integrity (DI) on quality assurance, while also highlighting the role of quality by design (QbD) principles. GAMP 5 is a widely used framework for validating automated systems that establishes quality assurance practices. DI guarantees the reliability of data collected throughout various stages of drug development. The integration of QbD principles promotes a systematic approach to development that emphasizes a deep understanding of critical quality attributes, risk management, and continuous improvement. With their implementation, organizations are able to meet regulatory requirements and provide safe medications to patients worldwide.

Rosacea Topical Treatment and Care: From Traditional to New Drug Delivery Systems.

Rosacea is a multifactorial chronic inflammatory dermatosis characterized by flushing, nontransient erythema, papules and pustules, telangiectasia, and phymatous alterations accompanied by itching, burning, or stinging, the pathophysiology of which is not yet fully understood. Conventional topical treatments usually show limited efficacy due to the physical barrier property of the skin that hinders skin penetration of the active ingredients, thereby hampering proper drug skin delivery and the respective therapeutic or cosmetic effects. New advances regarding the physiopathological understanding of the disease and the underlying mechanisms suggest the potential of new active ingredients as promising therapeutic and cosmetic approaches to this dermatosis. Additionally, the development of new drug delivery systems for skin delivery, particularly the potential of nanoparticles for the topical treatment and care of rosacea, has been described. Emphasis has been placed on their reduced nanometric size, which contributes to a significant improvement in the attainment of targeted skin drug delivery. In addition to the exposition of the known pathophysiology, epidemiology, diagnosis, and preventive measures, this Review covers the topical approaches used in the control of rosacea, including skin care, cosmetics, and topical therapies, as well as the future perspectives on these strategies.

The Role of Cyclodextrins in COVID-19 Therapy-A Literature Review.

Coronavirus disease-19 (COVID-19) emerged in December 2019 and quickly spread, giving rise to a pandemic crisis. Therefore, it triggered tireless efforts to identify the mechanisms of the disease, how to prevent and treat it, and to limit and hamper its global dissemination. Considering the above, the search for prophylactic approaches has led to a revolution in the reglementary pharmaceutical pipeline, with the approval of vaccines against COVID-19 in an unprecedented way. Moreover, a drug repurposing scheme using regulatory-approved antiretroviral agents is also being pursued. However, their physicochemical characteristics or reported adverse events have sometimes limited their use. Hence, nanotechnology has been employed to potentially overcome some of these challenges, particularly cyclodextrins. Cyclodextrins are cyclic oligosaccharides that present hydrophobic cavities suitable for complexing several drugs. This review, besides presenting studies on the inclusion of antiviral drugs in cyclodextrins, aims to summarize some currently available prophylactic and therapeutic schemes against COVID-19, highlighting those that already make use of cyclodextrins for their complexation. In addition, some new therapeutic approaches are underscored, and the potential application of cyclodextrins to increase their promising application against COVID-19 will be addressed. This review describes the instances in which the use of cyclodextrins promotes increased bioavailability, antiviral action, and the solubility of the drugs under analysis. The potential use of cyclodextrins as an active ingredient is also covered. Finally, toxicity and regulatory issues as well as future perspectives regarding the use of cyclodextrins in COVID-19 therapy will be provided.

Nanoclays for wound management applications.

Nanotechnology has been comprehensively applied as a new approach to managing wound healing. Particularly, nanoclays are being used to improve traditional wound healing approaches or new therapies. Nanoclays are nanoscale aluminosilicates with remarkable intrinsic properties, including the capacity to promote hemostatic response, anti-inflammatory effects, angiogenesis, and re-epithelization. The main purpose of the present review is focusing on skin lesions, post-surgical wounds, burn wounds, and chronic ulcer skin wounds that can be treated using nanoclays, not only as vehicles for therapeutic molecules' efficacy improvement but also alone due to their native beneficial features. A systematic search of the PubMed, ScienceDirect, Scopus, Web of Science, and Google Scholar databases revealed several studies satisfying the purpose of our study. In addition, the selected keywords were used to refine the information. Non-planar hydrous phyllosilicates have been compared with other nanoclays considering their acute specific surface area and loading capacity are strongly influenced by their structure. Nanocomposites in the powder form may be directly incorporated in polymers to form gels, biofilms, and scaffolds that may be adjustable to wound sites. Also, nanoclays can be directly incorporated into polymer mats. Regarding hydrogels/films and mats, nanoclays can improve their mechanical strength, thermal stability, viscosity, and cohesive strength. Additionally, nanoclays are able to control drug release, as well as their skin bioavailability, and seem to be promising candidates to overcome cytotoxicity problems; further in vivo toxicity studies are required.

Cyclodextrin-based dermatological formulations: Dermopharmaceutical and cosmetic applications.

The progress in new delivery systems for active ingredients has boosted the dermopharmaceutical and cosmetic fields by allowing formulations to display enhanced skin permeation capabilities. Cyclodextrins (CDs) are cyclic oligosaccharides able to form host-guest inclusion complexes with guest active molecules, resulting in improved physicochemical properties of such molecules. The incorporation of CDs in dermopharmaceutical and cosmetics formulations has received much attention since the late 1970 s by enhancing modulation of the passage through the skin and vectorization into the target site while simultaneously offering a biocompatible delivery system. This paper features the advantages of CDs in dermopharmaceutical and cosmetic applications, such as the improvement of the apparent solubility and the stability of the active ingredients, the possibility of masking unpleasant odors, among others that are be described, emphasizing that these versatile skin active ingredient carriers are strongly promising both in the treatment of skin diseases and in the improvement of cosmetic formulations.

Pharmacist Intervention in Portuguese Older Adult Care.

Healthy ageing has become one of the most significant challenges in a society with an increasing life expectancy. Older adults have a greater prevalence of chronic disease, with the need for multiple medications to appropriately control these issues. In addition to their health concerns, ageing individuals are prone to loneliness, dependence, and economic issues, which may affect their quality of life. Governments and health professionals worldwide have developed various strategies to promote active and healthy ageing to improve the quality of life of older adults. Pharmacists are highly qualified health professionals, easily accessible to the population, thus playing a pivotal role in medication management. Their proximity to the patient puts them in a unique position to provide education and training to improve therapeutic adherence and identify medication-related problems. This paper aims to address the importance of Portuguese community pharmacists in the medication management of older adults, emphasising their intervention in health promotion, patient education, medication-related problems, deprescription, dose administration aids, and medication review and reconciliation. We also discuss home delivery services and medication management in long-term care facilities.

Characterisation of institutionalised Portuguese older adult fallers: is there a place for pharmacist intervention? A preliminary study

Background: Falls are a major public health issue, given their prevalence and social impact. Older adults living in long-term care facilities (LTCF) are at greater risk of injury resulting from a fall due to multiple factors, such as nutritional, functional/cognitive impairment, postural instability, polypharmacy, and the presence of potentially inappropriate medications (PIMs). Medication management in LTCF is complex and often sub-optimal and might be crucial for falls. Pharmacist intervention is important, since they have a unique knowledge of medication. However, studies mapping the impact of pharmaceutical activities in Portuguese LTC settings are scarce. Objective: This study aims to assess the characteristics of older adult fallers living in LTFCs and examine the relationship between falling and several factors in this population. We also intend to explore the prevalence of PIMs and their relationship with the occurrence of falls. Methods: The study was conducted in two long-term care facilities for elderly people, in the central region of Portugal. We included patients aged 65 and older with no reduced mobility or physical weakness and with the ability to understand spoken and written Portuguese. The following information was assessed: sociodemographic characteristics, comorbidities, polypharmacy, fear of falling, functional, nutritional and cognitive status. PIMs were evaluated according to the Beers criteria (2019). Results: A total of 69 institutionalised older adults, 45 women and 24 men, with a mean age of 83.14 ± 8.87 years were included. The prevalence of falls was 21.74% Out of these, 46.67% (n=7) fell once, 13.33% (n=2) fell twice, and 40% (n=6) fell 3 or more times. Fallers were mainly women, had lower levels of education, were well nourished, had moderate to severe levels of dependence, and displayed moderate cognitive impairment. (AU)

Cyclodextrins as an encapsulation molecular strategy for volatile organic compounds- Pharmaceutical applications.

The use of essential oils has gained importance due to their wide range of biological properties. Essential oils comprise a complex mixture of volatile organic compounds (VOCs), so the study of VOCs as active pharmaceutical ingredients is often more precise and fruitful. VOCs are natural origin molecules that constitute a sustainable alternative to synthetic drugs due to their important therapeutic value. However, VOCs possess poor solubility in aqueous solutions, high volatility, and, consequently, low stability and bioavailability, limiting VOC handling in industry and their potential use in therapeutics, despite their promising biological properties. Thereby, cyclodextrins (CDs) have emerged as suitable carriers of VOCs, giving rise to so-called VOC/CD inclusion complexes. CDs constitute an inexpensive viable solution for encapsulating VOCs to improve their properties, namely their apparent solubility and stability toward pH, light, and temperature. This review provides a conceptual framework of several VOC/CD inclusion complexes developed. In addition, the most exploited preparation techniques and their influence on the values of encapsulation efficiency and formation constant (Kf) are highlighted. The most recent in vitro or in vivo biological experiments regarding VOC/CD inclusion complexes in the development of pharmaceutical products are also presented. Finally, the toxicological, and regulatory aspects are discussed.

Application of nanotechnology in management and treatment of diabetic wounds.

Diabetic wounds are one of the most common health problems worldwide, enhancing the demand for new management strategies. Nanotechnology, as a developing subject in diabetic wound healing, is proving to be a promising and effective tool in treatment and care. It is, therefore, necessary to ascertain the available and distinct nanosystems and evaluate their performance when topically applied to the injury site, especially in diabetic wound healing. Several active ingredients, including bioactive ingredients, growth factors, mesenchymal stem cells, nucleic acids, and drugs, benefit from improved properties when loaded into nanosystems. Given the risk of problems associated with systemic administration, the topical application should be considered, provided stability and efficacy are assured. After nanoencapsulation, active ingredients-loaded nanosystems have been showing remarkable features of biocompatibility, healing process hastening, angiogenesis, and extracellular matrix compounds synthesis stimulation, contributing to a decrease in wound inflammation. Despite limitations, nanotechnology has attracted widespread attention in the scientific community and seems to be a valuable technological ally in the treatment and dressing of diabetic wounds. The use of nanotechnology in topical applications enables efficient delivery of the active ingredients to the specific skin site, increasing their bioavailability, stability, and half-life time, without compromising their safety.

Nanocarriers for the topical treatment of psoriasis - pathophysiology, conventional treatments, nanotechnology, regulatory and toxicology.

Psoriasis is a chronic inflammatory non-contagious disease normally characterized by a multisystemic inflammation with reddish plaques and whitish scales with greater incidence in the knees, feet and hands, elbow, scalp, and sacral areas. The global incidence of psoriasis rounds about 2% of the population and it is established that the pathophysiology of this skin disease is quite complex and still misunderstood. Nowadays, this pathology still has no cure, however, efforts are being made to find more effective and safe treatments as well as trying to decrease the occurrence of crises and complications. Nanotechnology is increasingly becoming an innovating and promising new approach for the study of various dermatological diseases, such as psoriasis. In this case, the interest in the use of nanocarriers arises in order to decrease the side effects associated with conventional therapy, as well as improve its effectiveness. Nanotechnology allows for better solubility and better delivery of the drugs, as well as an increase in their tolerance. Besides psoriasis pathophysiology and its conventional treatments, this manuscript will also be present and discusse nanotechnological strategies for topical application that intend to increase the effectiveness of treatment, as well as its regulatory and toxicological context. Regulatory issues as well as nanotoxicological concerns and long-term safeness, both for the user and for the environment will be discussed.

Nanocarrier-based dermopharmaceutical formulations for the topical management of atopic dermatitis.

Atopic dermatitis (AD) is a chronic disease that affects the skin, and that is characterized by highly itchy inflammation, frequent eczematous lesions, and a fluctuating course. The current treatment consists of a multi-stage approach that aims to establish persistent disease control towards the improvement of the quality of life of the patients. Topical therapy is the basis of AD treatment, however, due to the difficulty of crossing the skin barrier, topical application of drugs remains a challenge. In fact, in addition to the low skin bioavailability, and limited accessibility to deeper skin of the drugs - due to difficulty in penetrating the epidermis - implemented drugs in the clinical are associated with serious adverse effects, which are responsible for safety and efficacy limitations, leading to a reduction in patients' compliance. Nanotechnology arises as an emerging approach for the treatment of AD, allowing for controlled release, targeted delivery, improved penetration, and bioavailability of drugs assets, resulting in marked improved therapeutic efficacy and reduction of adverse effects. Although its promising outputs, additional studies are needed to recognize the toxicological characteristics, cost-benefit, and long-term safety of nanocarriers applied to this end. Advanced drug delivery systems, particularly nanoemulsions, liposomes, ethosomes, transfersomes, solid lipid nanoparticles, nanostructured lipid carriers, nanocrystals, polymeric nanoparticles, and polymeric micelles have been used, and are thoroughly addressed in this review as promising nanoformulations towards the topical treatment of AD.

Characterisation of institutionalised Portuguese older adult fallers: is there a place for pharmacist intervention? A preliminary study.

Background: Falls are a major public health issue, given their prevalence and social impact. Older adults living in long-term care facilities (LTCF) are at greater risk of injury resulting from a fall due to multiple factors, such as nutritional, functional/cognitive impairment, postural instability, polypharmacy, and the presence of potentially inappropriate medications (PIMs). Medication management in LTCF is complex and often sub-optimal and might be crucial for falls. Pharmacist intervention is important, since they have a unique knowledge of medication. However, studies mapping the impact of pharmaceutical activities in Portuguese LTC settings are scarce. Objective: This study aims to assess the characteristics of older adult fallers living in LTFCs and examine the relationship between falling and several factors in this population. We also intend to explore the prevalence of PIMs and their relationship with the occurrence of falls. Methods: The study was conducted in two long-term care facilities for elderly people, in the central region of Portugal. We included patients aged 65 and older with no reduced mobility or physical weakness and with the ability to understand spoken and written Portuguese. The following information was assessed: sociodemographic characteristics, comorbidities, polypharmacy, fear of falling, functional, nutritional and cognitive status. PIMs were evaluated according to the Beers criteria (2019). Results: A total of 69 institutionalised older adults, 45 women and 24 men, with a mean age of 83.14 ± 8.87 years were included. The prevalence of falls was 21.74% Out of these, 46.67% (n=7) fell once, 13.33% (n=2) fell twice, and 40% (n=6) fell 3 or more times. Fallers were mainly women, had lower levels of education, were well nourished, had moderate to severe levels of dependence, and displayed moderate cognitive impairment. All adult fallers had a fear of falling. The main comorbidities of this population were related to the cardiovascular system. Polypharmacy was present in every patient, and at least one PIM was identified in 88.41% of the subjects. Fear of falling (FOF) and cognitive impairment (in subjects with 1 to 11 years of education) showed statistically significant associations with the occurrence of falls (p=0.005 and p=0.05, respectively). No significant differences were found between fallers and non-fallers for any other factors. Conclusions: This present study is a preliminary contribution to characterise a group of older adult fallers living in Portuguese LTCFs and demonstrated that fear of falling and cognitive impairment are associated with the occurrence of falls in this population. The high prevalence of polypharmacy and PIMs emphasises the need for tailored interventions featuring the collaboration of a pharmacist to optimise medication management in this population.

Nanotechnology-based formulations toward the improved topical delivery of anti-acne active ingredients.

Introduction: Acne vulgaris is a chronic inflammatory skin disorder that affects an extremely concerning percentage of teenagers (ca. 85%), gathering serious negative impacts on the social life and psychological well-being of individuals. Conventional topical formulations for acne show low tolerability and side effects, such as skin irritation, leading to a decrease in the user's adherence to therapy. Nanotechnology-based formulations were developed as new strategies for topical acne management, particularly to overcome the difficulties associated with conventional treatments.Areas covered: This paper presents a critical analysis of reviewed nanosized anti-acne technological strategies, strongly supporting controlled active ingredient release, improved skin permeation, and lower skin irritation. An updated regulatory framework, considering the promising applications in nanomedicine, and the toxicity of these nanosystems are also addressed.Expert opinion: Nanosystems evidence several advantages, attending to the possibility of controlled active ingredient release, better skin permeation, and lower skin irritation. However, novel nanotechnological strategies for acne treatment and care can lead to new side effects, but also environmental nano pollution. Little is known about the toxicology of these nanotechnology-based formulations, therefore, as future trends, more studies should be conducted to assure the consumers' health and environmental safety.

Ethosomes as Nanocarriers for the Development of Skin Delivery Formulations.

The use of nanotechnology has been extensively explored for developing efficient drug delivery systems towards topical and transdermal applications. Ethosomes constitute a vesicular nanocarrier containing a relatively high concentration of ethanol (20-45%). Ethanol is a well-known permeation enhancer, which confers ethosomes unique features, including high elasticity and deformability, allowing them to penetrate deeply across the skin and enhance drug permeation and deposition. The improved composition of ethosomes offer, thereby, significant advantages in the delivery of therapeutic agents over particularly the conventional liposomes regarding different pathologies, including acne, psoriasis, alopecia, skin infections, hormonal deficiencies, among others. This review provides a comprehensive overview of the ethosomal system and an assessment of its potential as an efficient nanocarrier towards the skin delivery of active ingredients. Special attention is given to the composition of ethosomes and the mechanism of skin permeation, as well as their potential applications in different pathologies, particularly skin pathologies (acne, psoriasis, atopic dermatitis, skin cancer and skin infections). Some examples of ethosome-based formulations for the management of skin disorders are also highlighted. Besides the need for further studies, particularly in humans, ethosomal-based formulations hold great promise in the skin delivery of active ingredients, which increasingly asserts oneself as a viable alternative to the oral route.