Anjaneyulu Udduttula

Osteoarthritis (OA) is a rapidly growing joint disease worldwide, and its chronic and progressive form can cause damage to the cartilage and subchondral bone, resulting in physical and economic suffering for affected individuals. So far, potential therapeutic approaches, such as systematic drug administration and intraarticular injections, have been used to treat OA and regenerate osteochondral defects, but they are palliative rather than curative. Thus, hydrogels with biologics (matrix-degrading enzyme inhibitors) and small molecules (growth factors, anti-inflammatory molecules) show promising results in preclinical studies but have failed in clinical practice due to inadequate patient benefits. Recently, bioinks have gained significant attention as regenerative biomaterials in tissue engineering due to their ability to contain cells and bioactive small molecules, such as proteins, peptides, and growth factors. Bioinks are developed using various polymers with crosslinkers. The crosslinkers play a crucial role in the formation of bioinks, which can be natural or synthetic (ionic, chemical, photo, etc.). However, extensive usage of crosslinkers limits the clinical application of bioinks due to compromising the ideal properties of bioinks, such as cytocompatibility, biodegradability, and biomechanical properties. Therefore, the potential solution to this problem is utilizing the click chemistry approach. The click chemistry strategy can achieve efficient bio-inks without compromising their intrinsic and optimal characteristics, as click reactions are rapid, spontaneous, and bioorthogonal, favoring the gelation time, rate of degradation, and cell viability. A few reports have delivered thorough information on click chemistry-induced hydrogels and bioinks for bone regeneration, but they are not specific to osteochondral regeneration. This review addresses this gap by exploring the fundamental concepts, challenges, and prospects of click chemistry, specifically its distinct click reactions, in developing bioinks and 3D bioprinting scaffolds for OA treatment and osteochondral regeneration. Furthermore, it addresses regulatory and clinical hurdles tied to bioink translation, providing an integrative overview of translational bioinks and tissue engineering strategies for cartilage and osteochondral regeneration.

The self-healing capacity of severely damaged articular cartilage is inherently limited due to weak cellular signaling, low cell turnover, poor extracellular matrix synthesis, and a lack of vascularization. Such damage to cartilage can lead to severe pain and the progression of osteoarthritis, significantly impacting patients' physical and mental well-being. Current surgical and nonsurgical interventions for repairing and regenerating cartilage tissue have shown inadequate long-term efficacy. Recently, the intrinsic electrical properties of bone tissue inspired researchers to focus on designing and fabricating regenerative biomaterials with bioelectrical properties such as piezoelectric, pyroelectric, ferroelectric, and dielectric for more effective treatment of bone defects. Among these electrical cues, piezoelectricity, in particular, plays a critical role in fracture healing and joint mechanics. The loss of cartilage alters biomechanics and may disrupt essential mechanotransduction pathways. However, the potential of these piezoelectrically active biomaterials with a combination of electroactive polymeric and biomimetic inorganic materials for regenerating cartilage and alleviating osteoarthritis has not been thoroughly explored. Therefore, developing natural, innovative, and biofunctional biomaterials with electrical properties is imperative to treating osteoarthritis effectively. The advancement of biomaterials with electroactive and other features offers the potential to transmit direct electrical signals to cells and stimulate faster tissue regeneration. In this review, we aim to understand and explore the electroactive properties of polymeric-based biomaterials by analyzing their potential applications and challenges in treating osteoarthritis. Specifically, we discussed how electroactive polymers can serve as bioinks for 3D bioprinting, hydrogels, coatings, and scaffolds in combination with bioactive inorganic materials to repair and regenerate articular cartilage. This comprehensive review will aid researchers in gaining a deeper understanding of electroactive polymers and provide insightful information for the development and advancement of electroactive biomaterials like piezo-activated next-generation biomaterials for the treatment of osteoarthritis in an effective manner.

Smart biomaterials have significantly impacted human healthcare by advancing the development of medical devices designed to function within human tissue, mimicking the behavior of natural tissues. While the intelligence of biomaterials has evolved from inert to active over the past few decades, smart biomaterials take this a step further by making their surfaces or bulk respond based on interactions with surrounding tissues, imparting outcomes similar to natural tissue functions. This interaction with the surrounding tissue helps in creating stimuli-responsive biomaterials, which can be useful in tissue engineering, regenerative medicine, autonomous drug delivery, orthopedics, and much more. Traditionally, material engineering focused on refining the static properties of biomaterials to accommodate them within the body without evoking an immune response, which was a major obstacle to their unrestricted operation. This review highlights and explains various engineering approaches currently under research for developing stimuli-responsive biomaterials that tune their outcomes based on responses to bodily factors like temperature, pH, and ion concentration or external factors like magnetism, light, and conductivity. Applications in soft and hard tissue engineering, 4D printing, and scaffold design are also discussed. The advanced application of microfluidics, like organ-on-a-chip models, extensively benefits from the intrinsic smart properties of biomaterials, which are also discussed below. The review further elaborates on how smart biomaterial engineering could revolutionize biosensor applications, thereby improving patient care quality. We delineate the limitations and key challenges associated with biomaterials, providing insights into the path forward and outlining future directions for developing next-generation biomaterials that will facilitate clinical translation.

Osteoporosis is the deterioration of bone mineral density (BMD) because of an imbalance between bone resorption and formation, which might happen due to lots of factors like age, hormonal imbalance, and several others. While this occurrence is prevalent in both genders, it is more common in women, especially postmenopausal women. It is an asymptomatic disease that is underlying until the first incidence of a fracture. The bone is weakened, making it more susceptible to fracture. Even a low trauma can result in a fracture, making osteoporosis an even more alarming disease. These fractures can sometimes be fatal or can make the patient bedridden. Osteoporosis is an understudied disease, and there are certain limitations in diagnosing and early-stage detection of this condition. The standard method of dual X-ray absorptiometry can be used to some extent and can be detected in standard radiographs after the deterioration of a significant amount of bone mass. Clinically assessing osteoporosis using biomarkers can still be challenging, as clinical tests can be expensive and cannot be accessed by most of the general population. In addition, manufacturing antibodies specific to these biomarkers can be a challenging, time-consuming, and expensive method. As an alternative to these antibodies, molecularly imprinted polymers (MIPs) can be used in the detection of these biomarkers. This Review provides a comprehensive exploration of bone formation, resorption, and remodeling processes, linking them to the pathophysiology of osteoporosis. It details biomarker-based detection and diagnosis methods, with a focus on MIPs for sensing CTX-1, NTX-1, and other biomarkers. The discussion compares traditional clinical practices with MIP-based sensors, revealing comparable sensitivity with identified limitations. Additionally, the Review contrasts antibody-functionalized sensors with MIPs. Finally, our Review concludes by highlighting the potential of MIPs in future early-stage osteoporosis detection.

Background: The repair of wounds usually caused by trauma or other chronic diseases remained challenging in clinics due to the potential risk of inflammation and inadequate tissue regenerative properties. Among them, the behaviour of immune cells, such as macrophages, is critical in tissue repair.Materials and methods: In this study, a water-soluble phosphocreatine-grafted methacryloyl chitosan (CSMP) was synthesized with a one-step lyophilization method, followed by the fabrication of CSMP hydrogel with a photocrosslinked method. The microstructure, water absorption and mechanical properties for the hydrogels were investigated. Then, the macrophages were co-cultured with hydrogels and the pro-inflammatory factors and polarization markers for these macrophages were detected through real-time quantitative polymerase chain reaction (RT-qPCR), Western blot (WB), and flow cytometry methods. Finally, the CSMP hydrogel was implanted in a wound defect area in mice to test its ability to promote wound healing.Results: The lyophilized CSMP hydrogel had a porous structure with pores ranging in size from 200 to 400 μm, which was larger than the CSM hydrogel’s. The lyophilized CSMP hydrogel possessed a higher water absorption rate compared with the CSM hydrogel. The compressive stress and modulus of these hydrogels were increased in the initial 7 days immersion and then gradually decreased during the in vitro immersion in PBS solution up to 21 days; the CSMP hydrogel showed a higher value in these parameters versus the CSM hydrogel. The CSMP hydrogel inhibited the expression of inflammatory factors such as interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α (TNF-α) in an in vitro study cocultured with pro-inflammatory factors in pre-treated bone marrow-derived macrophages (BMM). The mRNA sequencing results showed that the CSMP hydrogel might inhibit the macrophages’ M1 type polarization through the NF-κB signaling pathway. Furthermore, when compared to the control group, the CSMP hydrogel promoted more skin area repair in the mouse wound defect area, and inflammatory factors such as IL-1β, IL-6, and TNF-α were lower in the repaired tissue for the CSMP group.Conclusion: This phosphate-grafted chitosan hydrogel showed great promise for wound healing through regulating the macrophage’s phenotype via the NF-κB signaling pathway.