Biology subjects

Goodman, S. B.

Publications and source records attributed to Goodman, S. B..

5 recordsLinked to original sources

bioRxiv2022

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 cause 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-1{beta}, TNF- 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. Whereas 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 on the biocompatibility of biomaterials applied in medicine.

bioengineering↗

bioRxiv2022

Elevated oxidative phosphorylation is critical for immune cell activation by polyethylene wear particles

Chronic inflammation is a major concern after total joint replacements (TJRs), as it is associated with bone loss, limited bone-implant integration (osseointegration), implant loosening and failure. Inflammation around implants could be directed away from adverse outcomes and toward enhanced osseointegration and improved surgical outcome. Activated macrophages exposed to polyethylene particles play a dominant inflammatory role, and exhibit elevated mitochondrial oxidative phosphorylation (OXPHOS) whose role is unclear. By probing the contribution of the electron transport chain (ETC), we show that increased oxygen consumption does not contribute to bioenergetic (ATP) levels in fibroblasts and primary bone marrow-derived macrophages activated by polyethylene particles. Rather, it generates reactive oxygen species (ROS) at complex I by increasing mitochondrial membrane potential in macrophages. Inhibition of OXPHOS in a dosedependent manner without affecting glycolysis was accomplished by targeting complex I of the ETC using either rotenone or metformin. Metformin decreased mitochondrial ROS and, subsequently, expression of proinflammatory cytokines, including IL-1{beta}, IL-6 and MCP-1 but not TNF-a in macrophages. These results highlight the contribution of mitochondrial bioenergetics to activation of immune cells by polyethylene wear particles, offering new opportunities to modulate macrophage states toward desired clinical outcomes.

bioengineering↗

bioRxiv2022

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.

bioengineering↗

bioRxiv2022

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, we observed delayed cellular changes that were 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. Our 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.

bioengineering↗

bioRxiv2019

Exercise and angiotensin receptor blockade enhance recovery after orthopaedic trauma in mice by decreasing pain and improving muscle regeneration

Chronic pain and disability after limb injury are major public health problems. One key obstacle to addressing these adverse outcomes is that we do not know when exercise should be initiated or whether the beneficial effects of exercise can be reproduced using pharmacological tools. In these studies, we developed and used a murine model of orthopaedic trauma combining tibia fracture and pin fixation with tibialis anterior muscle damage. Behavioral measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microCT scanning, and muscle fiber size distribution as well as fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fiber size lasting up to 5 weeks from injury. We also observed that allowing \"late\" (weeks 1-2) rather than \"early\" (weeks 0-1) wheel running after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was also associated with lower levels of muscle fibrosis and a return towards normal muscle fiber diameters. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water blocked TGFbeta production while reducing both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes. Losartan may provide many of the same pain, functional and physiological outcomes by its regulation of TGFbeta signaling and is a viable candidate for translational studies.\n\nKey points summaryO_LIOur tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fiber loss.\nC_LIO_LIDelayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain\nC_LIO_LILosartan, an angiotensin-receptor blocker with antifibrotic abilities, recapitulates the effect of exercise on post-injury recovery\nC_LI

neuroscience↗