Illuminating an Invisible Epidemic: A Systemic Review of the Clinical and Economic Benefits of Early Diagnosis and Treatment in Inflammatory Disease and Related Syndromes.

Healthcare expenditures in the United States are growing at an alarming level with the Centers for Medicare and Medicaid Services (CMS) projecting that they will reach $5.7 trillion per year by 2026. Inflammatory diseases and related syndromes are growing in prevalence among Western societies. This growing population that affects close to 60 million people in the U.S. places a significant burden on the healthcare system. Characterized by relatively slow development, these diseases and syndromes prove challenging to diagnose, leading to delayed treatment against the backdrop of inevitable disability progression. Patients require healthcare attention but are initially hidden from clinician's view by the seemingly generalized, non-specific symptoms. It is imperative to identify and manage these underlying conditions to slow disease progression and reduce the likelihood that costly comorbidities will develop. Enhanced diagnostic criteria coupled with additional technological innovation to identify inflammatory conditions earlier is necessary and in the best interest of all healthcare stakeholders. The current total cost to the U.S. healthcare system is at least $90B dollars annually. Through unique analysis of financial cost drivers, this review identifies opportunities to improve clinical outcomes and help control these disease-related costs by 20% or more.

Compressive fatigue and fracture toughness behavior of injectable, settable bone cements.

Bone grafts used to repair weight-bearing tibial plateau fractures often experience cyclic loading, and there is a need for bone graft substitutes that prevent failure of fixation and subsequent morbidity. However, the specific mechanical properties required for resorbable grafts to optimize structural compatibility with native bone have yet to be established. While quasi-static tests are utilized to assess weight-bearing ability, compressive strength alone is a poor indicator of in vivo performance. In the present study, we investigated the effects of interfacial bonding on material properties under conditions that re-capitulate the cyclic loading associated with weight-bearing fractures. Dynamic compressive fatigue properties of polyurethane (PUR) composites made with either unmodified (U-) or polycaprolactone surface-modified (PCL-) 45S5 bioactive glass (BG) particles were compared to a commercially available calcium sulfate and phosphate-based (CaS/P) bone cement at physiologically relevant stresses (5-30 MPa). Fatigue resistance of PCL-BG/polymer composite was superior to that of the U-BG/polymer composite and the CaS/P cement at higher stress levels for each of the fatigue failure criteria, related to modulus, creep, and maximum displacement, and was comparable to human trabecular bone. Steady state creep and damage accumulation occurred during the fatigue life of the PCL-BG/polymer and CaS/P cement, whereas creep of U-BG/polymer primarily occurred at a low number of loading cycles. From crack propagation testing, fracture toughness or resistance to crack growth was significantly higher for the PCL-BG composite than for the other materials. Finally, the fatigue and fracture toughness properties were intermediate between those of trabecular and cortical bone. These findings highlight the potential of PCL-BG/polyurethane composites as weight-bearing bone grafts.

D-amino acid inhibits biofilm but not new bone formation in an ovine model.

BACKGROUND: Infectious complications of musculoskeletal trauma are an important factor contributing to patient morbidity. Biofilm-dispersive bone grafts augmented with D-amino acids (D-AAs) prevent biofilm formation in vitro and in vivo, but the effects of D-AAs on osteocompatibility and new bone formation have not been investigated. QUESTIONS/PURPOSES: We asked: (1) Do D-AAs hinder osteoblast and osteoclast differentiation in vitro? (2) Does local delivery of D-AAs from low-viscosity bone grafts inhibit new bone formation in a large-animal model? METHODS: Methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus clinical isolates, mouse bone marrow stromal cells, and osteoclast precursor cells were treated with an equal mass (1:1:1) mixture of D-Pro:D-Met:D-Phe. The effects of the D-AA dose on biofilm inhibition (n = 4), biofilm dispersion (n = 4), and bone marrow stromal cell proliferation (n = 3) were quantitatively measured by crystal violet staining. Osteoblast differentiation was quantitatively assessed by alkaline phosphatase staining, von Kossa staining, and quantitative reverse transcription for the osteogenic factors a1Col1 and Ocn (n = 3). Osteoclast differentiation was quantitatively measured by tartrate-resistant acid phosphatase staining (n = 3). Bone grafts augmented with 0 or 200 mmol/L D-AAs were injected in ovine femoral condyle defects in four sheep. New bone formation was evaluated by µCT and histology 4 months later. An a priori power analysis indicated that a sample size of four would detect a 7.5% difference of bone volume/total volume between groups assuming a mean and SD of 30% and 5%, respectively, with a power of 80% and an alpha level of 0.05 using a two-tailed t-test between the means of two independent samples. RESULTS: Bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation were inhibited at D-AAs concentrations of 27 mmol/L or greater in a dose-responsive manner in vitro (p < 0.05). In methicillin-sensitive and methicillin-resistant S aureus clinical isolates, D-AAs inhibited biofilm formation at concentrations of 13.5 mmol/L or greater in vitro (p < 0.05). Local delivery of D-AAs from low-viscosity grafts did not inhibit new bone formation in a large-animal model pilot study (0 mmol/L D-AAs: bone volume/total volume = 26.9% ± 4.1%; 200 mmol/L D-AAs: bone volume/total volume = 28.3% ± 15.4%; mean difference with 95% CI = -1.4; p = 0.13). CONCLUSIONS: D-AAs inhibit biofilm formation, bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation in vitro in a dose-responsive manner. Local delivery of D-AAs from bone grafts did not inhibit new bone formation in vivo at clinically relevant doses. CLINICAL RELEVANCE: Local delivery of D-AAs is an effective antibiofilm strategy that does not appear to inhibit bone repair. Longitudinal studies investigating bacterial burden, bone formation, and bone remodeling in contaminated defects as a function of D-AA dose are required to further support the use of D-AAs in the clinical management of infected open fractures.

Injectable foams for regenerative medicine.

The design of injectable biomaterials has attracted considerable attention in recent years. Many injectable biomaterials, such as hydrogels and calcium phosphate cements (CPCs), have nanoscale pores that limit the rate of cellular migration and proliferation. While introduction of macroporosity has been suggested to increase cellular infiltration and tissue healing, many conventional methods for generating macropores often require harsh processing conditions that preclude their use in injectable foams. In recent years, processes such as porogen leaching, gas foaming, and emulsion-templating have been adapted to generate macroporosity in injectable CPCs, hydrogels, and hydrophobic polymers. While some of the more mature injectable foam technologies have been evaluated in clinical trials, there are challenges remaining to be addressed, such as the biocompatibility and ultimate fate of the sacrificial phase used to generate pores within the foam after it sets in situ. Furthermore, while implantable scaffolds can be washed extensively to remove undesirable impurities, all of the components required to synthesize injectable foams must be injected into the defect. Thus, every compound in the foam must be biocompatible and noncytotoxic at the concentrations utilized. As future research addresses these critical challenges, injectable macroporous foams are anticipated to have an increasingly significant impact on improving patient outcomes for a number of clinical procedures.

Investigating the Effects of Surface-Initiated Polymerization of ε-Caprolactone to Bioactive Glass Particles on the Mechanical Properties of Settable Polymer/Ceramic Composites.

Injectable bone grafts with strength exceeding that of trabecular bone could improve the management of a number of orthopaedic conditions. Ceramic/polymer composites have been investigated as weight-bearing bone grafts, but they are typically weaker than trabecular bone due to poor interfacial bonding. We hypothesized that entrapment of surface-initiated poly(ε-caprolactone) (PCL) chains on 45S5 bioactive glass (BG) particles within an in situ-formed polymer network would enhance the mechanical properties of reactive BG/polymer composites. When the surface-initiated PCL molecular weight exceeded the molecular weight between crosslinks of the network, the compressive strength of the composites increased 6- to 10-fold. The torsional strength of the composites exceeded that of human trabecular bone by a factor of two. When injected into femoral condyle defects in rats, the composites supported new bone formation at 8 weeks. The initial bone-like strength of BG/polymer composites and their ability to remodel in vivo highlight their potential for development as injectable grafts for repair of weight-bearing bone defects.

Design and development of reactive injectable and settable polymeric biomaterials.

Injectable and settable biomaterials are a growing class of therapeutic technologies within the field of regenerative medicine. These materials offer advantages compared to prefabricated implants because of their ability to be utilized as part of noninvasive surgical procedures, fill complex defect shapes, cure in situ, and incorporate cells and other active biologics. However, there are significant technical barriers to clinical translation of injectable and settable biomaterials, such as achieving clinically relevant handling properties and benign reaction conditions. This review focuses on the engineering challenges associated with the design and development of injectable and chemically settable polymeric biomaterials. Additionally, specific examples of the diverse chemistries utilized to overcome these challenges are covered. The future translation of injectable and settable biomaterials is anticipated to improve patient outcomes for a number of clinical conditions.