Improving Biocompatibility for Next Generation of Metallic Implants.

The increasing need for joint replacement surgeries, musculoskeletal repairs, and orthodontics worldwide prompts emerging technologies to evolve with healthcare's changing landscape. Metallic orthopaedic materials have a shared application history with the aerospace industry, making them only partly efficient in the biomedical domain. However, suitability of metallic materials in bone tissue replacements and regenerative therapies remains unchallenged due to their superior mechanical properties, eventhough they are not perfectly biocompatible. Therefore, exploring ways to improve biocompatibility is the most critical step toward designing the next generation of metallic biomaterials. This review discusses methods of improving biocompatibility of metals used in biomedical devices using surface modification, bulk modification, and incorporation of biologics. Our investigation spans multiple length scales, from bulk metals to the effect of microporosities, surface nanoarchitecture, and biomolecules such as DNA incorporation for enhanced biological response in metallic materials. We examine recent technologies such as 3D printing in alloy design and storing surface charge on nanoarchitecture surfaces, metal-on-metal, and ceramic-on-metal coatings to present a coherent and comprehensive understanding of the subject. Finally, we consider the advantages and challenges of metallic biomaterials and identify future directions.

Treatment of Critical Size Femoral Bone Defects with Biomimetic Hybrid Scaffolds of 3D Plotted Calcium Phosphate Cement and Mineralized Collagen Matrix.

To treat critical-size bone defects, composite materials and tissue-engineered bone grafts play important roles in bone repair materials. The purpose of this study was to investigate the bone regenerative potential of hybrid scaffolds consisting of macroporous calcium phosphate cement (CPC) and microporous mineralized collagen matrix (MCM). Hybrid scaffolds were synthetized by 3D plotting CPC and then filling with MCM (MCM-CPC group) and implanted into a 5 mm critical size femoral defect in rats. Defects left empty (control group) as well as defects treated with scaffolds made of CPC only (CPC group) and MCM only (MCM group) served as controls. Eight weeks after surgery, micro-computed tomography scans and histological analysis were performed to analyze the newly formed bone, the degree of defect healing and the activity of osteoclasts. Mechanical stability was tested by 3-point-bending of the explanted femora. Compared with the other groups, more newly formed bone was found within MCM-CPC scaffolds. The new bone tissue had a clamp-like structure which was fully connected to the hybrid scaffolds and thereby enhanced the biomechanical strength. Together, the biomimetic hybrid MCM-CPC scaffolds enhanced bone defect healing by improved osseointegration and their differentiated degradation provides spatial effects in the process of critical-bone defect healing.

3D Printing in alloy design to improve biocompatibility in metallic implants.

3D Printing (3DP) or additive manufacturing (AM) enables parts with complex shapes, design flexibility, and customization opportunities for defect specific patient-matched implants. 3DP or AM also offers a design platform that can be used to innovate novel alloys for application-specific compositional modifications. In medical applications, the biological response from a host tissue depends on a biomaterial's structural and compositional properties in the physiological environment. Application of 3DP can pave the way towards manufacturing innovative metallic implants, combining structural variations at different length scales and tailored compositions designed for specific biological responses. This study shows how 3DP can be used to design metallic alloys for orthopedic and dental applications with improved biocompatibility using in vitro and in vivo studies. Titanium (Ti) and its alloys are used extensively in biomedical devices due to excellent fatigue and corrosion resistance and good strength to weight ratio. However, Ti alloys' in vivo biological response is poor due to its bioinert surface. Different coatings and surface modification techniques are currently being used to improve the biocompatibility of Ti implants. We focused our efforts on improving Ti's biocompatibility via a combination of tantalum (Ta) chemistry in Ti, the addition of designed micro-porosity, and nanoscale surface modification to enhance both in vitro cytocompatibility and early stage in vivo osseointegration, which was studied in rat and rabbit distal femur models.

Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles.

Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mφs). On the other hand, the response of Mφs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mφs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mφs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mφs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mφs may be a critical target for the clinical treatment of cPE induced fibrosis.

Protocol-Driven Revision for Stiffness After Total Knee Arthroplasty Improves Motion and Clinical Outcomes.

BACKGROUND: Stiffness after revision total knee arthroplasty (TKA) is a difficult problem without a well-defined treatment algorithm. The purpose of this study was to evaluate the results of revision TKA for stiffness within the context of differential component replacement. METHODS: Consecutive patients who underwent revision TKA were retrospectively identified and included those who received debridement and polyethylene liner exchange alone, revision of only one of the femoral or tibial fixed components, or revision of all components. Preoperative and postoperative range of motion and Knee Society score (KSS) were collected. RESULTS: Sixty-nine knees were included in the study group with a mean follow-up of 43 months (range, 12-205 months). The mean prerevision flexion contracture of 17° improved to 5° after surgical intervention (P < .001). Similarly, mean flexion and motion arc improved from 70° to 92° and from 53° to 87°, respectively (P < .001). Mean KSS knee scores improved from 42 to 70 and KSS function scores improved from 41 to 68 (P < .001). Mean arc of motion improved by 45° in patients who underwent complete component revision, 32° with component retention, and 29° with single component revision (P = .046). KSS knee scores improved by 34, 25, and 28 points in these respective groups (P = .049). KSS function scores improved by 33, 27, and 25 points (P = .077). CONCLUSION: Revision surgery with or without component revision can improve motion and function in patients with stiffness after TKA. Complete component revision may offer the largest improvements in these outcome measures in properly selected patients.

Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components.

BACKGROUND: Loosening and periprosthetic osteolysis are some of the most common long-term complications after hip arthroplasty. The decision-making process and surgical treatment options are controversial. METHODS: We retrospectively reviewed 96 acetabular revisions (91 patients) performed between 2002 and 2012, with a minimum of 2 years of follow-up and a mean of 5.7 years of follow-up. Clinical outcome was assessed using the Harris Hip Score. The size and location of osteolytic lesions were evaluated using the preoperative radiographs; healing of the defects was categorized using a standardized protocol. RESULTS: Thirty-three (34.4%) hips had isolated liner exchanges (ILEs), 10 (10.4%) hips had cemented liners into well-fixed shells (CLS), 45 (46.9%) hips had full acetabular revisions (FARs), and 8 (8.3%) hips had revision with a roof ring/antiprotrusio cage (RWC). All procedures showed significant improvement in Harris Hip Score after revision (P ≤ .001). Fifteen patients had moderate residual pain (pain score ≤20): 8 (24%) ILE, 3 (30%) CLS, and 4 (9%) FAR. Complete bone defect healing after grafting was lower with acetabular component retention procedures (ILE and CLS; 27%) compared with full acetabular component revision procedures (FAR and RWC; 57%). Fifteen patients underwent reoperation: 3 ILE, 1 CLS, 8 FAR, and 3 RWC. CONCLUSION: Acetabular component retention demonstrates a low risk of reoperation; however, residual pain and limited potential for bone graft incorporation are a concern. FAR is technically challenging and may have an elevated risk of reoperation; however, higher degrees of bone graft incorporation and satisfactory clinical outcome can be expected.

Treatment of Periprosthetic Knee Infection With a Two-stage Protocol Using Static Spacers.

BACKGROUND: Two-stage exchange arthroplasty is a standard approach for treating total knee arthroplasty periprosthetic joint infection in the United States, but whether this should be performed with a static antibiotic spacer or an articulating one that allows range of motion before reimplantation remains controversial. It is unclear if the advantages of articulating spacers (easier surgical exposure during reimplantation and improved postoperative flexion) outweigh the disadvantages of increased cost and complexity in the setting of similar rates of infection eradication. QUESTIONS/PURPOSES: The purposes of this study were (1) to determine the ultimate range of motion; and (2) to determine the proportion of patients who remained free of infection at a minimum 2 years after treatment with static antibiotic spacers as part of a two-stage revision TKA for the treatment of periprosthetic joint infection. METHODS: Between 1999 and 2011, we treated 121 patients with chronically infected TKAs, of whom three had medical comorbidities precluding a two-stage exchange, four had died before 2-year followup for reasons other than the surgical intervention, and seven were lost to followup. The remaining 107 patients (109 knees; 53 men and 54 women) were treated using a two-stage approach with static spacers and are evaluated here at a mean of 3.7 years (range, 2.0-9.8 years); no patients were treated with articulating spacers during this study period. Twenty-five percent (27 of 109) of the organisms isolated the first-stage procedure were resistant to methicillin and/or vancomycin. Median age at the time of reimplantation was 67 years (range, 42-89 years). Range of motion was measured by an independent physical therapist with a standard goniometer. Knee Society knee and function scores were calculated before the first stage and at the 2-year mark. Because many of these patients were treated before consensus definitions of infection were established, we made the diagnosis of infection (and established that a patient was believed to be free of infection) using the approaches prevalent at that time, which generally included presence of a sinus tract communicating directly with the implant, two positive tissue cultures, or a combination of cultures, fluid analysis, and serology. RESULTS: Postoperatively, 67 knees had full extension and no patients had a flexion contracture > 10°. Median flexion was 100° (range, 60°-139°). Thirty-nine knees had postoperative flexion > 120°. Ninety-four percent of patients were clinically free of infection at last followup. CONCLUSIONS: Our two-stage exchange protocol with static spacers yielded comparable flexion and infection eradication when compared with other recent studies that have used articulating spacers. The large proportion of resistant organisms is alarming. Future multicenter studies should compare static with articulating spacers and should evaluate both cost and efficacy, because our study suggests that adequate range of motion can be achieved without the added cost of the articulating spacer. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Tibiofemoral Dislocation After Total Knee Arthroplasty.

BACKGROUND: Tibiofemoral dislocation after total knee arthroplasty (TKA) is a rare complication. Published case reports describe fewer than 6 patients, making conclusions about the etiology, epidemiology, complications, and treatment of tibiofemoral dislocation difficult. This case series highlights common demographic features, potential causes, and difficulties during the management of tibiofemoral dislocations after TKA. METHODS: Between 2005 and 2014, 14 patients presented to our institution with a tibiofemoral dislocation. Patients were excluded if they had patellofemoral dislocation or subluxation without a tibiofemoral dislocation. We retrospectively reviewed patient demographics, time to first dislocation, number of dislocations, time to surgical intervention, complications, and potential etiologies of tibiofemoral dislocation. RESULTS: Twelve of 14 patients were female. Their mean body mass index was 33 ± 10 kg/m(2). Thirteen of 14 patients had a mean of 2.0 ± 1.4 dislocations. Four patients dislocated due to polyethylene damage and 5 due to ligamentous incompetence. Twelve of 14 patients required open surgical intervention. Complications in this patient population were common with 3 cases of infection, 7 cases of multiple dislocation, 2 cases of popliteal artery laceration, 1 case receiving a fusion, and 1 case receiving an amputation. CONCLUSION: Patients with tibiofemoral dislocation after TKA are predominantly obese, female, and have a high risk for complications. They dislocate predominantly because of polyethylene damage or ligamentous incompetence. Re-dislocation is common if treated with closed reduction alone.

Current modes of failure in TKA: infection, instability, and stiffness predominate.

BACKGROUND: Historically, polyethylene wear and its sequelae (osteolysis, late instability, aseptic loosening) were common causes for revision total knee arthroplasty (TKA). Recently, polyethylene manufacturing has become more consistent; furthermore, a clearer understanding of the importance of oxidation on polyethylene performance led to packaging of the polyethylene bearings in an inert environment. This improved the quality and consistency of polyethylene used in TKA, raising the question of whether different failure modes now predominate after TKA. QUESTIONS/PURPOSES: The purpose of this study was to determine the current reasons for (1) early and (2) late failures after TKA at one high-volume arthroplasty center. METHODS: We reviewed all first-time revision TKAs performed between 2001 and 2011 at one institution, yielding a group of 253 revision TKAs in 251 patients. Mean age at the time of revision was 64 years (SD 10 years). Mean time to revision was 35 months (SD 23 months). Preoperative evaluations, laboratory data, radiographs, and intraoperative findings were used to determine causes for revision. Early failure was defined as revision within 2 years of the index procedure. The primary failure mechanism was determined by the operating surgeon. RESULTS: Early failure accounted for 46% (116 of 253) of all revisions with infection (28 of 116 [24%]), instability (30 of 116 [26%]), and stiffness (21 of 116 [18%]) being the leading causes. Late failure accounted for 54% (137 of 253) of all revisions with the most common causes including infection (34 of 137 [25%]), instability (24 of 137 [18%]), and stiffness (19 of 253 [14%]). Polyethylene wear was implicated as the failure mechanism in 2% of early cases (two of 116) and 9% of late cases (13 of 137). CONCLUSIONS: In contrast to previous studies, wear-related implant failure in TKA was relatively uncommon in this series. Changes in polyethylene manufacturing, sterilization, and storage may have accounted for some of this difference; however, longer-term followup will be required to verify this finding. Infection, instability, and stiffness represent the most common causes of early and late failure. Strategies to improve outcomes in TKA should be aimed at infection prophylaxis and treatment, surgical technique, and patient selection. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Polyethylene wear and osteolysis is associated with high revision rate of a small sized porous coated THA in patients with hip dysplasia.

The outcome of 25 primary THAs in patients with hip dysplasia using the AML Bantam femoral stem (DePuy) is reported. Age at operation averaged 43 ± 10 years. Twenty-two of 25 stems were cementless. All cementless acetabular components had conventional or cross-linked polyethylene and screws. Follow-up averaged 11 ± 5 years (range 4-18). Four cementless stems were revised after 3, 4, 8, and 9 years; 2/3 cemented stems were revised at 8 and 18 years. Femoral revisions demonstrated extensive conventional polyethylene wear, periprosthetic osteolysis and loosening. Five entire cups were revised for wear and loosening; four liners were replaced. Harris Hip Scores for patients with retained stems went from 43 ± 12 to 85 ± 13. High revision rates with the proximally porous coated Bantam stem are due to loss of fixation, often associated with polyethylene wear and osteolysis.

Outcome of porous tantalum acetabular components for Paprosky type 3 and 4 acetabular defects.

Porous tantalum acetabular implants provide a potential solution for dealing with significant acetabular bone loss. This study reviews 24 acetabular revisions using tantalum implants for Paprosky type 3 and 4 defects. The mean Harris Hip Score improved from 35 ± 19 (range, 4-71) to 88 ± 14 (range, 41-100), p < 0.0001. Postoperative radiographs showed radiolucent lines in 14 hips with a mean width of 1.3 ± 1.0 mm (range, 0.27-4.37 mm). No gaps enlarged and 71% of them disappeared at a mean of 13 ± 10 months (range, 3-29 months). At a mean follow-up of 37 ± 14 months (range, 24-66 months), 22 reconstructions showed radiograpic evidence of osseointegration (92%). The two failures were secondary to septic loosening. When dealing with severe acetabular bone loss, porous tantalum acetabular components show promising short-term results.

Direct subcutaneous injection of polyethylene particles over the murine calvaria results in dramatic osteolysis.

PURPOSE: The murine calvarial model has been widely employed for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening of total joint replacements. Classically, this model uses an open surgical technique in which polyethylene (PE) particles are directly spread over the calvarium for the induction of osteolysis. We evaluated a minimally invasive modification of the calvarial model by using a direct subcutaneous injection of PE particles. METHODS: Polyethylene (PE) particles were injected subcutaneously over the calvaria of C57BL6J ten-week-old mice ("injection" group) or were implanted after surgical exposure of the calvaria ("open" group) (n = 5/group). For each group, five additional mice received no particles and served as controls. Particle-induced osteolysis was evaluated two weeks after the procedure using high-definition microCT imaging. RESULTS: Polyethylene particle injection over the calvaria resulted in a 40% ± 1.8% decrease in the bone volume fraction (BVF), compared to controls. Using the "open surgical technique", the BVF decreased by 16% ± 3.8% as compared to controls (p < 0.0001). CONCLUSIONS: Direct subcutaneous injection of PE particles over the murine calvaria produced more profound resorption of bone. Polyethylene particle implantation by injection is less invasive and reliably induces osteolysis to a greater degree than the open technique. This subcutaneous injection method will prove useful for repetitive injections of particles, and the assessment of potential local or systemic therapies.

Wear debris in metal-on-metal bearings and modular junctions : What have we learned from the last decades?

Metal-on-metal (MoM) bearing hip arthroplasty saw increasing utilization and peaked in the 1990s and early 2000s. Although the linear and volumetric wear rate for a MoM bearings was lower than its polyethylene counterpart, metal ion particles were found to be approximately 10â€¯× smaller and 500â€¯× higher in quantity compared to polyethylene wear debris. Research into these articulations have demonstrated their relationship to the formation of lymphocyte-mediated adverse local tissue reactions. The work-up for metal particle-associated conditions (metallosis) includes a thorough patient history and physical examination, blood laboratory studies for metal ion concentrations, and advanced imaging studies including magnetic resonance imaging (MRI). The treatment of metallosis and adverse local tissue reactions ranges from close serial observation to extensive debridement and full revision of arthroplasty components, when indicated.

Glycolytic reprogramming underlies immune cell activation by polyethylene wear particles.

Primary total joint arthroplasties (TJAs) are widely and successfully applied reconstructive procedures to treat end-stage arthritis. Nearly 50 % of TJAs are now performed in young patients, posing a new challenge: performing TJAs which last a lifetime. The urgency is justified because subsequent TJAs are costlier and fraught with higher complication rates, not to mention the toll taken on patients and their families. Polyethylene particles, generated by wear at joint articulations, drive aseptic loosening by inciting insidious inflammation associated with surrounding bone loss. Down modulating polyethylene particle-induced inflammation enhances integration of implants to bone (osseointegration), preventing loosening. A promising immunomodulation strategy could leverage immune cell metabolism, however, the role of immunometabolism in polyethylene particle-induced inflammation is unknown. Our findings reveal that immune cells exposed to sterile or contaminated polyethylene particles show fundamentally altered metabolism, resulting in glycolytic reprogramming. Inhibiting glycolysis controlled inflammation, inducing a pro-regenerative phenotype that could enhance osseointegration.

Stereochemistry Determines Immune Cellular Responses to Polylactide Implants.

Repeating l- and d-chiral configurations determine polylactide (PLA) stereochemistry, which affects its thermal and physicochemical properties, including degradation profiles. Clinically, degradation of implanted PLA biomaterials promotes prolonged inflammation and excessive fibrosis, but the role of PLA stereochemistry is unclear. Additionally, although PLA of varied stereochemistries causes differential immune responses in vivo, this observation has yet to be effectively modeled in vitro. A bioenergetic model was applied to study immune cellular responses to PLA containing >99% l-lactide (PLLA), >99% d-lactide (PDLA), and a 50/50 melt-blend of PLLA and PDLA (stereocomplex PLA). Stereocomplex PLA breakdown products increased IL-1ß, TNF-α, and IL-6 protein levels but not MCP-1. Expression of these proinflammatory cytokines is mechanistically driven by increases in glycolysis in primary macrophages. In contrast, PLLA and PDLA degradation products selectively increase MCP-1 protein expression. Although both oxidative phosphorylation and glycolysis are increased with PDLA, only oxidative phosphorylation is increased with PLLA. For each biomaterial, glycolytic inhibition reduces proinflammatory cytokines and markedly increases anti-inflammatory (IL-10) protein levels; differential metabolic changes in fibroblasts were observed. These findings provide mechanistic explanations for the diverse immune responses to PLA of different stereochemistries and underscore the pivotal role of immunometabolism in the biocompatibility of biomaterials applied in medicine.

Therapeutic effects of MSCs, genetically modified MSCs, and NFĸB-inhibitor on chronic inflammatory osteolysis in aged mice.

The number of total joint replacements is increasing, especially in elderly patients, and so too are implant-related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF-ĸB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically-modified NF-ĸB sensing interleukin-4 over-secreting MSCs (IL4-MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15-17 months old) for 6 weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast-like cells, increased alkaline phosphatase (ALP)-positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4-MSCs significantly decreased osteoclast-like cells and increased the M2/M1 ratio, with a greater trend for IL4-MSCs than MSCs. MSCs significantly increased ALP-positive area and BMD values compared with the control. The IL4-MSCs demonstrated higher values for both ALP-positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4-MSCs on chronic inflammatory osteolysis in aged mice. The two MSC-based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4-MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle-associated inflammatory osteolysis after arthroplasty in the elderly.

Metabolic profile of mesenchymal stromal cells and macrophages in the presence of polyethylene particles in a 3D model.

BACKGROUND: Continuous cross talk between MSCs and macrophages is integral to acute and chronic inflammation resulting from contaminated polyethylene particles (cPE); however, the effect of this inflammatory microenvironment on mitochondrial metabolism has not been fully elucidated. We hypothesized that (a) exposure to cPE leads to impaired mitochondrial metabolism and glycolytic reprogramming and (b) macrophages play a key role in this pathway. METHODS: We cultured MSCs with/without uncommitted M0 macrophages, with/without cPE in 3-dimensional gelatin methacrylate (3D GelMA) constructs/scaffolds. We evaluated mitochondrial function (membrane potential and reactive oxygen species-ROS production), metabolic pathways for adenosine triphosphate (ATP) production (glycolysis or oxidative phosphorylation) and response to stress mechanisms. We also studied macrophage polarization toward the pro-inflammatory M1 or the anti-inflammatory M2 phenotype and the osteogenic differentiation of MSCs. RESULTS: Exposure to cPE impaired mitochondrial metabolism of MSCs; addition of M0 macrophages restored healthy mitochondrial function. Macrophages exposed to cPE-induced glycolytic reprogramming, but also initiated a response to this stress to restore mitochondrial biogenesis and homeostatic oxidative phosphorylation. Uncommitted M0 macrophages in coculture with MSC polarized to both M1 and M2 phenotypes. Osteogenesis was comparable among groups after 21 days. CONCLUSION: This work confirmed that cPE exposure triggers impaired mitochondrial metabolism and glycolytic reprogramming in a 3D coculture model of MSCs and macrophages and demonstrated that macrophages cocultured with MSCs undergo metabolic changes to maintain energy production and restore homeostatic metabolism.

Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming.

Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses. Using a bioenergetic model, delayed cellular changes were observed that are not apparent in the short-term. Amorphous and semi-crystalline PLA degradation products, including monomeric l-lactic acid, mechanistically remodel metabolism in cells leading to a reactive immune microenvironment characterized by elevated proinflammatory cytokines. Selective inhibition of metabolic reprogramming and altered bioenergetics both reduce these undesirable high cytokine levels and stimulate anti-inflammatory signals. The results present a new biocompatibility paradigm by identifying metabolism as a target for immunomodulation to increase tolerance to biomaterials, ensuring safe clinical application of PLA-based implants for soft- and hard-tissue regeneration, and advancing nanomedicine and drug delivery.

Unexpected failure of highly cross-linked polyethylene acetabular liner.

Highly cross-linked polyethylene (HXPE) in total hip arthroplasty has been shown to decrease wear rate compared with conventional liner. However, it has some disadvantages in that the mechanical properties cause early failure of the implant. This case report presents an unexpected failure of total hip arthroplasty in a 72-year-old woman that occurred at 20 months postsurgery. Operative findings revealed fracture of superior rim at locking groove of liner. We concluded that the failure was caused by decreased mechanical properties of highly cross-linked polyethylene, less thickness of polyethylene, more vertical cup, and use of large femoral head.