Hyaluronic acid-British anti-Lewisite as a safer chelation therapy for the treatment of arthroplasty-related metallosis.

Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects-including peri-implant toxicity, aseptic loosening, and pseudotumor-as well as systemic toxic effects-including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC50 levels of cobalt) and enhances the rate of clearance of cobalt in vivo (t1/2 from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint.

Corrosion of Metals During Use in Arthroplasty.

Arthroplasty implants can undergo corrosion at the modular components, trunnion, and hinges, owing to implant material makeup, micromotion, and interaction with body fluid. In this review, various mechanisms of corrosion in arthroplasty were explored with suggestions on means of improvement. We identified 10 methods including pitting, crevice, mechanically assisted crevice corrosion, fretting, fretting initiated crevice corrosion, mechanically assisted taper corrosion, galvanic corrosion, stress/tension, fatigue corrosion, and inflammatory cell induced corrosion. The position of implants on the galvanic series, and their ability to maintain passivation contribute to their longevity in service. Due to the relative motion of arthroplastic components, bio-tribocorrosion may disrupt passive oxide films, and pitting is initiated at interfaces. Thus, corrosion in arthroplasty as an electrochemical phenomenon mainly starts on one spot and progresses in 3 steps: (1) the oxidative dissolution of metal from implant surfaces into the aqueous active environment, releasing cations, (2) the attraction of electrons to the opposite charge created at another point of the implant surface, producing current flow, and (3) the formation of oxides of metal and metal hydroxides deposited as rust at the surface of the implant. Recent innovations in material manufacturing continue to improve the efficiency of arthroplasty; however, the component parts remain susceptible to bio-tribocorrosion. Thus, a complete eradication of corrosion in arthroplasty would require futuristic materials with improvement in recent materials and designs, derived from knowledge of existing retrieved implants, and strategies to provide overall surface finishes that protect against bio-tribocorrosion.

Regenerative engineering of long bones using the small molecule forskolin.

Bone grafting procedures have become increasingly common in the United States, with approximately 500,000 cases occurring each year at a societal cost exceeding $2.4 billion. Recombinant human bone morphogenetic proteins (rhBMPs) are therapeutic agents that have been widely used by orthopedic surgeons to stimulate bone tissue formation alone and when paired with biomaterials. However, significant limitations such as immunogenicity, high production cost, and ectopic bone growth from these therapies remain. Therefore, efforts have been made to discover and repurpose osteoinductive small-molecule therapeutics to promote bone regeneration. Previously, we have demonstrated that a single-dose treatment with the small-molecule forskolin for just 24 h induces osteogenic differentiation of rabbit bone marrow-derived stem cells in vitro, while mitigating adverse side effects attributed with prolonged small-molecule treatment schemes. In this study, we engineered a composite fibrin-PLGA [poly(lactide-co-glycolide)]-sintered microsphere scaffold for the localized, short-term delivery of the osteoinductive small molecule, forskolin. In vitro characterization studies showed that forskolin released out of the fibrin gel within the first 24 h and retained its bioactivity toward osteogenic differentiation of bone marrow-derived stem cells. The forskolin-loaded fibrin-PLGA scaffold was also able to guide bone formation in a 3-mo rabbit radial critical-sized defect model comparable to recombinant human bone morphogenetic protein-2 (rhBMP-2) treatment, as demonstrated through histological and mechanical evaluation, with minimal systemic off-target side effects. Together, these results demonstrate the successful application of an innovative small-molecule treatment approach within long bone critical-sized defects.

Oxygen-Generating Biomaterials for Translational Bone Regenerative Engineering.

Successful regeneration of critical-size defects remains one of the significant challenges in regenerative engineering. These large-scale bone defects are difficult to regenerate and are often reconstructed with matrices that do not provide adequate oxygen levels to stem cells involved in the regeneration process. Hypoxia-induced necrosis predominantly occurs in the center of large matrices since the host tissue's local vasculature fails to provide sufficient nutrients and oxygen. Indeed, utilizing oxygen-generating materials can overcome the central hypoxic region, induce tissue in-growth, and increase the quality of life for patients with extensive tissue damage. This article reviews recent advances in oxygen-generating biomaterials for translational bone regenerative engineering. We discussed different oxygen-releasing and delivery methods, fabrication methods for oxygen-releasing matrices, biology, oxygen's role in bone regeneration, and emerging new oxygen delivery methods that could potentially be used for bone regenerative engineering.

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.

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.

Isolation and Culture of Periosteum-Derived Progenitor Cells from Mice.

This chapter describes the methods of isolation of mouse periosteal progenitor cells. There are three basic methods utilized. The bone grafting method was developed utilizing the fracture healing process to expand the progenitor populations. Bone capping methods requires enzymatic digestion and purification of cells from the native periosteum, while the Egression/Explant method requires the least manipulation with placement of cortical bone fragments with attached periosteum in a culture dish. Various cell surface antibodies have been employed over the years to characterize periosteum derived progenitor cells, but the most consistent minimal criteria was recommended by the International Society for Cellular Therapy. Confirmation of the multipotent status of these isolated cells can be achieved by differentiation into the three basic mesodermal lineages in vitro.

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.

Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model.

OBJECTIVES: In this study, Adipose stem cells (ADSC) and bone marrow stem cells (BMSC), multipotent adult cells with the potentials for cartilage regenerations were induced to chondrogenic lineage and used for cartilage regenerations in surgically induced osteoarthritis in sheep model. METHODS: Osteoarthritis was induced at the right knee of sheep by complete resection of the anterior cruciate ligament and medial meniscus following a 3-weeks exercise regimen. Stem cells from experimental sheep were culture expanded and induced to chondrogenic lineage. Test sheep received a single dose of 2 × 10(7) autologous PKH26-labelled, chondrogenically induced ADSCs or BMSCs as 5 mls injection, while controls received 5 mls culture medium. RESULTS: The proliferation rate of ADSCs 34.4 ± 1.6 hr was significantly higher than that of the BMSCs 48.8 ± 5.3 hr (P = 0.008). Chondrogenic induced BMSCs had significantly higher expressions of chondrogenic specific genes (Collagen II, SOX9 and Aggrecan) compared to chondrogenic ADSCs (P = 0.031, 0.010 and 0.013). Grossly, the treated knee joints showed regenerated de novo cartilages within 6 weeks post-treatment. On the International Cartilage Repair Society grade scores, chondrogenically induced ADSCs and BMSCs groups had significantly lower scores than controls (P = 0.0001 and 0.0001). Fluorescence of the tracking dye (PKH26) in the injected cells showed that they had populated the damaged area of cartilage. Histological staining revealed loosely packed matrixes of de novo cartilages and immunostaining demonstrated the presence of cartilage specific proteins, Collagen II and SOX9. CONCLUSION: Autologous chondrogenically induced ADSCs and BMSCs could be promising cell sources for cartilage regeneration in osteoarthritis.