Functions and Effectiveness of Unloader, Patellofemoral, and Knee Sleeve Orthoses: A Review.

Background: Knee orthoses have been extensively used as a nonsurgical approach to improving knee deficiencies. Currently, arthritic knee conditions remain the leading cause of disability, and this number is expected to increase. As the use of knee orthoses varies widely, so has their effectiveness which is still largely debatable. Here, we present the functions and effectiveness of the three most prominent knee orthotic models dedicated to supporting knee osteoarthritis-unloader, patellofemoral, and knee sleeves. Purpose/Research Question: Considering the depth and diversity of the many clinical studies and documented laboratory reports published to date, this literature review was created to educate the clinician, patient, and researcher on common knee orthoses used for the management of arthritic knee conditions. In doing so, we discuss their design, biomechanical effects, and clinical efficacy, as well as broader outcomes, limitations, and recommendations for use. Results/Synthesis: The knee orthoses discussed within the scope of this paper are dedicated to protecting the knee against strenuous compressive loads that may affect the patellofemoral and tibiofemoral joints of the knee. Since the knee has multiple axes of motion and articulating surfaces that experience different loads during functional activities, it can be implied that, to a large extent, knee brace designs can differ drastically. Unloader knee orthoses are designed to decrease tibiofemoral and patellofemoral joint pressures. Patellofemoral knee orthoses are designed to decrease strain on the patellofemoral and quadriceps tendons while stabilizing the patella. Knee sleeves are designed to stabilize movements, reduce pain in joints, and improve proprioception across the knee joint. Conclusion: Although patients often report benefits from wearing braces, these benefits have not been confirmed by clinicians and scientific investigators. Results from these three orthosis types show that clinical efficacy is still elusive due to the different methodologies used by researchers. Layman Summary: Knee orthoses also referred to as knee brace are commonly used for support and stability of the knee. Unloader knee braces are designed to relieve and support those suffering from knee osteoarthritis by improving physical impairment and reducing pain. Patellofemoral knee braces aim to help patients manage patellofemoral pain syndrome. Rehabilitative compression sleeves, also known as knee sleeves, are often used to assist patients suffering from knee pain and laxity. Important findings on the three knee braces discussed show discrepancies in results. Their effectiveness and validity are yet to be understood.

Stromal Vascular Fraction for Osteoarthritis of the Knee Regenerative Engineering.

Purpose: The knee joint is prone to osteoarthritis (OA) due to its anatomical position, and several reports have implicated the imbalance between catabolic and anabolic processes within the joint as the main culprit, thus leading to investigations towards attenuation of these inflammatory signals for OA treatment. In this review, we have explored clinical evidence supporting the use of stromal vascular fraction (SVF), known for its anti-inflammatory characteristics for the treatment of OA. Methods: Searches were made on PubMed, PMC, and Google Scholar with the keywords "adipose fraction knee regeneration, and stromal vascular fraction knee regeneration, and limiting searches within 2017-2020. Results: Frequently found interventions include cultured adipose-derived stem cells (ADSCs), SVF, and the micronized/microfragmented adipose tissue-stromal vascular fraction (MAT-SVF). Clinical data reported that joints treated with SVF provided a better quality of life to patients. Currently, MAT-SVF obtained and administered at the point of care is approved by the Food and Drug Administration (FDA), but more studies including manufacturing validation, safety, and proof of pharmacological activity are needed for SVF. The mechanism of action of MAT-SVF is also not fully understood. However, the current hypothesis indicates a direct adherence and integration with the degenerative host tissue, and/or trophic effects resulting from the secretome of constituent cells. Conclusion: Our review of the literature on stromal vascular fraction and related therapy use has found evidence of efficacy in results. More research and clinical patient follow-up are needed to determine the proper place of these therapies in the treatment of osteoarthritis of the knee. Lay Summary: Reports have implicated the increased inflammatory proteins within the joints as the main cause of osteoarthritis (OA). This has attracted interest towards addressing these inflammatory proteins as a way of treatment for OA. The concentrated cell-packed portion of the adipose product stromal vascular fraction (SVF) from liposuction or other methods possesses anti-inflammatory effects and has been acclaimed to heal OA. Thus, we searched for clinical evidence supporting their use, for OA treatment through examining the literature. Data from various hospitals support that joints treated with SVF provided a better quality of life to patients. Currently, there is at least one version of these products that are obtained and given back to patients during a single clinic visit, approved by the FDA.

Osmotic-controlled release oral tablets: technology and functional insights.

In recent years, oral osmotic tablets have sparked a therapeutic paradigm for controlled-release dosage forms due to their intrinsic insensitivity to physiological and physicochemical factors. Despite these benefits, the design of an optimal osmotic technology is precluded by various challenges. These limitations include manufacturing complexity, the lack of understanding of the functional mechanics, and inadequate optimization for the desired bio-performance. This paper systematically reviews the development of an osmotic-driven drug delivery system and the strategy for a zero-order release profile with an emphasis on swellable core technology. We discuss the applicability of the various types of osmotic tablets, their suitability to specific needs, and factors that drive the technology selection. Finally, we review the challenges, opportunities, and future perspectives associated with osmotic tablets.

In Vivo Evaluation of the Regenerative Capability of Glycylglycine Ethyl Ester-Substituted Polyphosphazene and Poly(lactic-co-glycolic acid) Blends: A Rabbit Critical-Sized Bone Defect Model.

In an effort to understand the biological capability of polyphosphazene-based polymers, three-dimensional biomimetic bone scaffolds were fabricated using the blends of poly[(glycine ethylglycinato)75(phenylphenoxy)25]phosphazene (PNGEGPhPh) and poly(lactic-co-glycolic acid) (PLGA), and an in vivo evaluation was performed in a rabbit critical-sized bone defect model. The matrices constructed from PNGEGPhPh-PLGA blends were surgically implanted into 15 mm critical-sized radial defects of the rabbits as structural templates for bone tissue regeneration. PLGA, which is the most commonly used synthetic bone graft substitute, was used as a control in this study. Radiological and histological analyses demonstrated that PNGEGPhPh-PLGA blends exhibited favorable in vivo biocompatibility and osteoconductivity, as the newly designed matrices allowed new bone formation to occur without adverse immunoreactions. The X-ray images of the blends showed higher levels of radiodensity than that of the pristine PLGA, indicating higher rates of new bone formation and regeneration. Micro-computed tomography quantification revealed that new bone volume fractions were significantly higher for the PNGEGPhPh-PLGA blends than for the PLGA controls after 4 weeks. The new bone volume increased linearly with increasing time points, with the new tissues observed throughout the defect area for the blend and only at the implant site's extremes for the PLGA control. Histologically, the polyphosphazene system appeared to show tissue responses and bone ingrowths superior to PLGA. By the end of the study, the defects with PNGEGPhPh-PLGA scaffolds exhibited evidence of effective bone tissue ingrowth and minimal inflammatory responses. Thus, polyphosphazene-containing biomaterials have excellent translational potential for use in bone regenerative engineering applications.

The Mechanism of Metallosis After Total Hip Arthroplasty.

Metallosis is defined as the accumulation and deposition of metallic particles secondary to abnormal wear from prosthetic implants that may be visualized as abnormal macroscopic staining of periprosthetic soft tissues. This phenomenon occurs secondary to the release of metal ions and particles from metal-on-metal hip implants in patients with end-stage osteoarthritis. Ions and particles shed from implants can lead to local inflammation of surrounding tissue and less commonly, very rare systemic manifestations may occur in various organ systems. With the incidence of total hip arthroplasty increasing as well as rates of revisions due to prosthesis failure from previous metal-on-metal implants, metallosis has become an important area of research. Bodily fluids are electrochemically active and react with biomedical implants. Particles, especially cobalt and chromium, are released from implants as they abrade against one another into the surrounding tissues. The body's normal defense mechanism becomes activated, which can elicit a cascade of events, leading to inflammation of the immediate surrounding tissues and eventually implant failure. In this review, various mechanisms of metallosis are explored. Focus was placed on the atomic and molecular makeup of medical implants, the component/surgical associated factors, cellular responses, wear, tribocorrosion, joint loading, and fluid pressure associated with implantation. Current treatment guidelines for failed implants include revision surgery. An alternative treatment could be chelation therapy, which may drive future studies.

A Regenerative Polymer Blend Composed of Glycylglycine ethyl ester-substituted Polyphosphazene and Poly (lactic-co-glycolic acid).

In the pursuit of continuous improvement in the area of biomaterial design, blends of mixed-substituent polyphosphazenes and poly (lactic acid-glycolic acid) (PLGA) were prepared, and their morphology of phase distributions for the first time was studied. The degradation mechanism and osteocompatibility of the blends were also evaluated for their use as regenerative materials. Poly [(ethyl phenylalanato)25(glycine ethyl glycinato)75phosphazene](PNEPAGEG) and poly [(glycine ethyl glycinato)75(phenylphenoxy)25phosphazene](PNGEGPhPh) were blended with PLGA at various weight ratios to yield different blends, namely PNEPAGEG-PLGA 25:75, PNEPAGEG-PLGA 50:50, PNGEGPhPh-PLGA 25:75, and PNGEGPhPh-PLGA 50:50. The molecular interactions, domain sizes, and phase distributions of the blends were confirmed by atomic force microscopy (AFM) as the PNEPAGEG-PLGA and PNGEGPhPh-PLGA blends showed different domain sizes and phase distributions. Due to the extensive hydrogen bonding within the two polymer components, PNEPAGEG-PLGA exhibited small-sized domains and well-distributed morphology. While for the PNGEGPhPh-PLGA blends, the presence of phenylphenol (PhPh) caused the formation of PLGA large-sized domains as the PLGA formed a continuous phase and PNGEGPhPh constituted a dispersed phase. In addition to AFM results, scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDS), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and Fourier transform infrared spectroscopy (FTIR) results demonstrated the miscibility of the blends. The PNEPAGEG-PLGA and PNGEGPhPh-PLGA blends presented in situ 3D interconnected porous structures upon degradation in phosphate-buffered saline (PBS) media at 37°C. However, the blends showed different mechanistic pathways to the formations of the pores. The difference in the erosion patterns could be attributed to the nature of molecular attractions that exist in the blends. Furthermore, the novel blends were able to support cell growth as compared to PLGA, and accommodate cell infiltrations, which ultimately augmented surface area for better cell-material interactions.

Nanofiber Technology for Regenerative Engineering.

Regenerative engineering is powerfully emerging as a successful strategy for the regeneration of complex tissues and biological organs using a convergent approach that integrates several fields of expertise. This innovative and disruptive approach has spurred the demands for more choice of biomaterials with distinctive biological recognition properties. An ideal biomaterial is one that closely mimics the hierarchical architecture and features of the extracellular matrices (ECM) of native tissues. Nanofabrication technology presents an excellent springboard for the development of nanofiber scaffolds that can have positive interactions in the immediate cellular environment and stimulate specific regenerative cascades at the molecular level to yield healthy tissues. This paper systematically reviews the electrospinning process technology and its utility in matrix-based regenerative engineering, focusing mainly on musculoskeletal tissues. It briefly outlines the electrospinning/three-dimensional printing system duality and concludes with a discussion on the technology outlook and future directions of nanofiber matrices.

Polyphosphazene polymers: The next generation of biomaterials for regenerative engineering and therapeutic drug delivery.

The demand for new biomaterials in several biomedical applications, such as regenerative engineering and drug delivery, has increased over the past two decades due to emerging technological advances in biomedicine. Degradable polymeric biomaterials continue to play a significant role as scaffolding materials and drug devices. Polyphosphazene platform is a subject of broad interest, as it presents an avenue for attaining versatile polymeric materials with excellent structure and property tunability, and high functional diversity. Macromolecular substitution enables the facile attachment of different organic groups and drug molecules to the polyphosphazene backbone for the development of a broad class of materials. These materials are more biocompatible than traditional biomaterials, mixable with other clinically relevant polymers to obtain new materials and exhibit unique erosion with near-neutral degradation products. Hence, polyphosphazene represents the next generation of biomaterials. In this review, the authors systematically discuss the synthetic design, structure-property relationships, and the promising potentials of polyphosphazenes in regenerative engineering and drug delivery.

Biomedical applications of polyphosphazenes.

Ever since the pioneering research efforts on their utility in biomedicine, polyphosphazene polymers have witnessed enormous growth and expansion in several biomedical applications due to their unique properties. The development of this exceptional biodegradable system with extraordinary design flexibility, property tunability and neutral bioactivity could stimulate an unprecedented paradigm in biomaterial design. Thus, polyphosphazenes are, undoubtedly, the next-generation biomaterials. This editorial provides a brief perspective on the promising prospects of polyphosphazene-based biomaterials for medical device technology, focusing mainly on the authors' work on this particular polymeric system.

Generational Biodegradable and Regenerative Polyphosphazene Polymers and their Blends with Poly (lactic-co-glycolic acid).

New fields such as regenerative engineering have driven the design of advanced biomaterials with a wide range of properties. Regenerative engineering is a multidisciplinary approach that integrates the fields of advanced materials science and engineering, stem cell science, physics, developmental biology, and clinical translation for the regeneration of complex tissues. The complexity and demands of this innovative approach have motivated the synthesis of new polymeric materials that can be customized to meet application-specific needs. Polyphosphazene polymers represent this fundamental change and are gaining renewed interest as biomaterials due to their outstanding synthetic flexibility, neutral bioactivity (buffering degradation products), and tunable properties across the range. Polyphosphazenes are a unique class of polymers composed of an inorganic backbone with alternating phosphorus and nitrogen atoms. Each phosphorus atom bears two substituents, with a wide variety of side groups available for property optimization. Polyphosphazenes have been investigated as potential biomaterials for regenerative engineering. Polyphosphazenes for use in regenerative applications have evolved as a class to include different generations of degradable polymers. The first generation of polyphosphazenes for tissue regeneration entailed the use of hydrolytically active side groups such as imidazole, lactate, glycolate, glucosyl, or glyceryl groups. These side groups were selected based on their ability to sensitize the polymer backbone to hydrolysis, which allowed them to break down into non-toxic small molecules that could be metabolized or excreted. The second generation of degradable polyphosphazenes developed consisted of polymers with amino acid ester side groups. When blended with poly (lactic acid-co-glycolic acid) (PLGA), the feasibility of neutralizing acidic degradation products of PLGA was demonstrated. The blends formed were mostly partially miscible. The desire to improve miscibility led to the design of the third generation of degradable polyphosphazenes by incorporating dipeptide side groups which impart significant hydrogen bonding capability to the polymer for the formation of completely miscible polyphosphazene-PLGA blends. Blend system of the dipeptide-based polyphosphazene and PLGA exhibit a unique degradation behavior that allows the formation of interconnected porous structures upon degradation. These inherent pore-forming properties have distinguished degradable polyphosphazenes as a potentially important class of biomaterials for further study. The design considerations and strategies for the different generations of degradable polyphosphazenes and future directions are discussed.

POLYMERIC BIOMATERIALS FOR SCAFFOLD-BASED BONE REGENERATIVE ENGINEERING.

Reconstruction of large bone defects resulting from trauma, neoplasm, or infection is a challenging problem in reconstructive surgery. The need for bone grafting has been increasing steadily partly because of our enhanced capability to salvage limbs after major bone loss. Engineered bone graft substitutes can have advantages such as lack of antigenicity, high availability, and varying properties depending on the applications chosen for use. These favorable attributes have contributed to the rise of scaffold-based polymeric tissue regeneration. Critical components in the scaffold-based polymeric regenerative engineering approach often include 1. The existence of biodegradable polymeric porous structures with properties selected to promote tissue regeneration and while providing appropriate mechanical support during tissue regeneration. 2. Cellular populations that can influence and enhance regeneration. 3. The use of growth and morphogenetic factors which can influence cellular migration, differentiation and tissue regeneration in vivo. Biodegradable polymers constitute an attractive class of biomaterials for the development of scaffolds due to their flexibility in chemistry and their ability to produce biocompatible degradation products. This paper presents an overview of polymeric scaffold-based bone tissue regeneration and reviews approaches as well as the particular roles of biodegradable polymers currently in use.

Synthesis, Physicochemical Analysis, and Side Group Optimization of Degradable Dipeptide-Based Polyphosphazenes as Potential Regenerative Biomaterials.

We report the synthesis and physicochemical analysis of mixed-substituent dipeptide-based polyphosphazene polymers, poly[(glycineethylglycinato) x (phenylphenoxy) y phosphazene] (PNGEG x PhPh y ) and poly[(ethylphenylalanato) x (glycineethylglycinato) y phosphazene] (PNEPA x GEG y ), using glycylglycine ethyl ester (GEG) as the primary substituent side group and cosubstituting with phenylphenol (PhPh) and phenylalanine ethyl ester (EPA), respectively. The suitability of the cosubstituted polyphosphazenes to regenerative engineering was evaluated. The physicochemical evaluation revealed that the molecular weights, glass transition temperatures, hydrophilicity, and mechanical properties could be modulated by varying the compositions of the side groups to obtain a variety of properties. The PNEPA25GEG75 and PNGEG75PhPh25 polymers exhibited the most promising physicochemical properties. These two polymers were further subjected to in vitro hydrolysis and cell proliferation studies using poly(lactic-co-glycolic acid) (PLAGA) as a control. The hydrolysis experiments revealed that the two polymers hydrolyzed to near-neutral pH media (~5.3 to 7.0) in a relatively slow fashion, whereas a pH value as low as 2.2 was obtained for the PLAGA media over 12 weeks of degradation study. Furthermore, the two polymers showed continuous MC3T3 cell proliferation and growth in comparison to PLAGA over a 21-day culture period. These findings establish that cosubstitution of different side groups of polyphosphazenes and exploitation of the hydrogen-bonding capacity of peptide bonds in GEG offer a flexible tool that can be employed to make new and fascinating polymeric biomaterials with different and tailored properties that can suit different regenerative needs.

Biodegradable Polyphosphazene-Based Blends for Regenerative Engineering.

The occurrence of musculoskeletal tissue injury or disease and the subsequent functional impairment is at an alarming rate. It continues to be one of the most challenging problems in the human health care. Regenerative engineering offers a promising transdisciplinary strategy for tissues regeneration based on the convergence of tissue engineering, advanced materials science, stem cell science, developmental biology and clinical translation. Biomaterials are emerging as extracellular-mimicking matrices designed to provide instructive cues to control cell behavior and ultimately, be applied as therapies to regenerate damaged tissues. Biodegradable polymers constitute an attractive class of biomaterials for the development of scaffolds due to their flexibility in chemistry and the ability to be excreted or resorbed by the body. Herein, the focus will be on biodegradable polyphosphazene-based blend systems. The synthetic flexibility of polyphosphazene, combined with the unique inorganic backbone, has provided a springboard for more research and subsequent development of numerous novel materials that are capable of forming miscible blends with poly (lactide-co-glycolide) (PLAGA). Laurencin and co-workers has demonstrated the exploitation of the synthetic flexibility of Polyphosphazene that will allow the design of novel polymers, which can form miscible blends with PLAGA for biomedical applications. These novel blends, due to their well-tuned biodegradability, and mechanical and biological properties coupled with the buffering capacity of the degradation products, constitute ideal materials for regeneration of various musculoskeletal tissues. LAY SUMMARY: Regenerative engineering aims to regenerate complex tissues to address the clinical challenge of organ damage. Tissue engineering has largely focused on the restoration and repair of individual tissues and organs, but over the past 25 years, scientific, engineering, and medical advances have led to the introduction of this new approach which involves the regeneration of complex tissues and biological systems such as a knee or a whole limb. While a number of excellent advanced biomaterials have been developed, the choice of biomaterials, however, has increased over the past years to include polymers that can be designed with a range of mechanical properties, degradation rates, and chemical functionality. The polyphosphazenes are one good example. Their chemical versatility and hydrogen bonding capability encourages blending with other biologically relevant polymers. The further development of Polyphosphazene-based blends will present a wide spectrum of advanced biomaterials that can be used as scaffolds for regenerative engineering and as well as other biomedical applications.