Three-Dimensionally Printed Scaffolds and Drug Delivery Systems in Treatment of Osteoporosis

Abstract

The increasing incidence of osteoporotic fractures determines ongoing research on new methods and strategies for improving the difficult healing process of this type of fracture. Osteoporotic patients suffer from the intense side effects of accustomed drug treatment and its systemic distribution in the body. To overcome these drawbacks, besides searching for new drugs, 3D-printed scaffolds and drug delivery systems have started to be increasingly seen as the main strategy employed against osteoporosis. Three-dimensionally printed scaffolds can be tailored in intricate designs and make use of nanoscale topographical and biochemical cues able to enhance bone tissue regeneration. Research regarding drug delivery systems is exploring bold new ways of targeting bone tissue, making use of designs involving nanoparticles and intricate encapsulation and support methods. The local administration of treatment with the help of a scaffold-based drug delivery system looks like the best option through its use of the advantages of both structures. Biomimetic systems are considered the future norm in the field, while stimuli-responsiveness opens the door for the next level of efficiency, patient compliance, and a drastic reduction in side effects. The successful approval of these products still requires numerous challenges throughout the development and regulatory processes, but the interest and effort in this direction are high. This review explored various strategies for managing osteoporosis, emphasizing the use of scaffolds for targeted drug delivery to bone tissue. Instead of covering the whole subject, we focused on the most important aspects, with the intention to provide an up-to-date and useful introduction to the management of osteoporosis.

Introduction

Osteoporosis (OP) is a systemic skeletal chronic condition characterized by decreased bone mass and quality (microarchitectural changes) [1]. OP negatively influences bone regeneration potential, bone mineral density (BMD), and the ability to obtain proper mechanical stability for fracture healing [2]. As life expectancy increases, osteoporotic elderly patients, which represent a larger portion of the population, have a higher incidence of fractures not determined by significant trauma [1,3]. Also, there is an increasing incidence of osteoporotic fractures at all ages [4]. Statistical data indicate that approximately one-third of women and one-fifth of men worldwide either have or will develop OP [5]. Because such fractures usually do not heal, their healing time increases, or they heal inadequately, there is a high risk of subsequent fractures [6,7] and hundreds of billions of USD annually worldwide are spent for repair and regeneration [8]. Although both the public and academia have a high interest in the disease’s treatment [9,10], it is important to note that OP most often remains undiagnosed until an osteoporotic fracture occurs [11]. In the domain of medical imaging, central dual-energy X-ray absorptiometry (DXA) has been recognized by the World Health Organization as the gold standard for assessing BMD and diagnosing OP in postmenopausal women [12]. BMD represents a measure of both the quantity of bone tissue and its degree of mineralization, being influenced by the peak bone mass achieved during growth and the subsequent bone loss associated with aging, and is expressed as grams of mineral per square centimeter of scanned bone (g/cm2) [13]. A normal BMD is defined by a T-score of −1.0 or higher. Conversely, a T-score between −1.0 and −2.5 indicates low bone mass, or osteopenia, whereas a T-score of −2.5 or lower is diagnostic of OP [12]. OP may accelerate after the implantation of osteosynthesis devices, joint prostheses, or dental implants, causing poorer bone–implant adhesion and an increased probability of bone fracture [14].

Bone tissue is being continuously remodeled by bone-forming osteoblasts and bone-resorbing osteoclasts in healthy individuals in order to repair micro-damage and adapt to mechanical and metabolic needs [4]. In the initial stage of remodeling, old bone is removed by the osteoclasts, activated by the osteocytes, and, in the following stage, osteoblasts fill the areas previously resorbed by the osteoclasts [14]. Osteoblasts maintain and form healthy bone tissue through protein synthesis and matrix secretion [15]. New bone tissue comprise mostly collagen osteoid that is progressively mineralized [14]. Once an imbalance emerges between formation and resorption, mass loss begins, which leads to lower bone density compared to normal bone tissue. The excessive activation of osteoclasts and the increased osteoclast-induced bone turnover are the causes of this change in the normal equilibrium of the bone [6]. Important bone density loss usually affects the hips and vertebral bodies [16], and the common fragility fracture sites are the vertebral bodies, the proximal femur, the proximal humerus, wrist, forearm, and the distal radius [1,7]. OP-related fractures have significantly increased morbidity and have led to debilitating sequelae, like chronic pain, balance disorders [17], and premature mortality [18]. Although the majority of bone defects can heal naturally, the regeneration process may become challenging when OP leads to inadequate bone formation.

Primary OP, with distinguishable juvenile, postmenopausal, and senile forms, is the most frequent type. Secondary OP is derived from several other disease categories, such as endocrine (hypogonadism, hypocortisolism, hyperparathyroidism, acromegaly, diabetes mellitus), hematological, gastrointestinal, rheumatic, and kidney disease, or from the usage of drugs like glucocorticoids, anticoagulants, and diuretics [1,12]. The development of OP is influenced by multiple factors, including genetic predisposition, hormonal imbalances, the natural aging process, inadequate nutrition, and lifestyle habits such as smoking, reduced physical activity, or the usage of steroids [5,14]. In postmenopausal OP, the pathogenesis is associated with estrogen depletion, which enhances the bone loss that occurs with aging [1,18]. Estrogen depletion influences all bone cells by regulating cell differentiation and apoptosis and by changing the expression of estrogen response target genes, causing a faster increase in bone resorption [15].

Because the actual treatment of OP can cause significant side effects [5], research has focused on developing new safer drugs or drug formulations, on delivery methods of drugs at the defect site, avoiding as many side effects as possible, and on the development of 3D scaffolds that influence local bone tissue metabolism, promoting osteogenic induction. Conventionally, drug administration follows a systemic approach, where medications enter the bloodstream and circulate throughout the body. However, this method has several disadvantages, including potential toxicity, as well as insufficient penetration into the target tissue. Extensive damage can make traditional treatments ineffective, while bone grafting may be restricted due to the need for additional surgical procedures and the risk of disease transmission [19]. In such scenarios, bone tissue engineering has become a promising alternative, employing cells, scaffolds, and growth factors to restore damaged bone tissue, together with DDS. Various alternative treatment strategies for bone defects, such as distraction osteogenesis, growth factor delivery, electrical stimulation, the Masquelet-induced membrane technique, and their combinations have also emerged in recent years. Nonetheless, their clinical translation is hindered by prolonged treatment durations and a high risk of complications [20].

Growing interest in tissue engineering due to a growing demand for biodegradable biomaterials capable of promoting the repair, replacement, or restoration of hard tissues has resulted in the development of exciting potential alternatives to autogenous bone grafts [21]. Bone scaffolds designed for biomedical applications serve as three-dimensional (3D) frameworks that support bone regeneration and promote the formation of new bone tissue. It is important to note that personalized treatment could be considered depending on the physical conditions of the patient [18]. Bone tissue engineering not only refers to the use of a scaffolding material to induce the formation of bone from the surrounding tissue but also its acting as a carrier for implanted bone cells or other therapeutic agents [22]. Smart-material-based strategies encompass a variety of innovative applications, including smart scaffolds and stem cell constructs, intelligent drug delivery systems, and stimuli-responsive materials. These advanced biomaterials not only facilitate the targeted delivery of stem cells and enable the controlled spatial and temporal release of drugs and bioactive agents but also play a crucial role in biofilm modulation and infection prevention at wound sites [8]. Through the study of the characteristics and commonalities of diseases, the design of drug delivery systems (DDSs) has become a hot research topic at present. In the case of bone, with its limited blood supply, drugs administrated systemically are exposed to various physicochemical and biological factors that affect their bioavailability [23]. DDSs are designed to enhance the targeted delivery of specific therapeutic agents to desired sites more efficiently [24]. DDSs are especially useful when the drug has dose-limiting side effects, a narrow therapeutic window, and/or a short half-life that makes maintaining a proper drug concentration difficult [25]. Overall, nanostructured DDSs represent innovative alternatives for osteoporosis therapy by enabling controlled drug release, enhancing local drug concentration, reducing side effects, and promoting bone healing [26]. In this article, we have reviewed some of the most frequently employed anti-OP drugs; the main principles of bone scaffold development, as well as the most important biomaterials used for these scaffolds; and the main principles behind DDS development, as well as the most important DDS used in bone treatment. Finally, we have mentioned a few future perspectives regarding the strategies employed for fighting OP.

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Excipients mentioned in the paper beside others: Compritol^®888 ATO, Precirol^® ATO5, cetyl alcohol, cetylpalmitate, glyceryl monostearate, trimyristin/Dynasan^®114, tristearin/Dynasan^®118

Codrea, C.I.; Fruth, V. Three-Dimensionally Printed Scaffolds and Drug Delivery Systems in Treatment of Osteoporosis. Biomimetics 2025, 10, 429. https://doi.org/10.3390/biomimetics10070429

Read also our introduction article on 3D Printing here: