A Narrative Review of Ultrasound-Guided and Landmark-based Percutaneous Cryoneurolysis for the Management of Acute and Chronic Pain.

PURPOSE OF REVIEW: Cryoneurolysis refers to the process of reversibly ablating peripheral nerves with extremely cold temperatures to provide analgesia for weeks to months. With ultrasound-guidance or landmark-based techniques, it is an effective modality for managing both acute and chronic pain. In this review, we summarize the reported literature behind its potential applications and efficacy. RECENT FINDINGS: Here, we summarize several studies (from case reports to clinical trials) describing the use of ultrasound-guided and landmark-based cryoneurolysis for acute and chronic pain. Acute pain indications included pain related to knee arthroplasty, limb amputations, mastectomies, shoulder surgery, rib fractures, and burn. Chronic pain indications included chronic knee pain (due to osteoarthritis), shoulder pain, painful neuropathies, postmastectomy pain syndrome, phantom limb pain, facial pain/headaches, foot/ankle pain, inguinal pain, and sacroiliac joint pain. For both acute and chronic pain indications, more high quality randomized controlled clinical trials are needed to definitively assess the efficacy of cryoneurolysis versus other standard therapies for a multitude of pain conditions.

Access to Neurorehabilitation Interdisciplinary Outpatient Programs in British Columbia.

This survey explored access to British Columbia (BC) hospital-based neurorehabilitation outpatient programs (HB-NROPs). Fifteen rehabilitation-focused healthcare providers were interviewed. Wait times for HB-NROPs were up to 3 months for initial appointments, and inclusion criteria were variable. Two HB-NROPs had occasional access to specialized physicians. Informal communication methods were preferred modes of collaboration. BC HB-NROPs varied in access, use of interdisciplinary care, and outcome measures used to measure performance. The lack of coverage for nonphysician services may be a barrier to collaborative care in the community. Future projects should explore solutions to improve funding and equal access to BC HB-NROPs.

Spasticity Management Teams, Evaluations, and Tools: A Canadian Cross-Sectional Survey.

OBJECTIVE: The objective of this study is to determine the physical evaluations and assessment tools used by a group of Canadian healthcare professionals treating adults with spasticity. METHODS: A cross-sectional web-based 19-question survey was developed to determine the types of physical evaluations, tone-related impairment measurements, and assessment tools used in the management of adults with spasticity. The survey was distributed to healthcare professionals from the Canadian Advances in Neuro-Orthopedics for Spasticity Congress database. RESULTS: Eighty study participants (61 physiatrists and 19 other healthcare professionals) completed the survey and were included. Nearly half (46.3%, 37/80) of the participants reported having an inter- or trans-disciplinary team managing individuals with spasticity. Visual observation of movement, available range of motion determination, tone during velocity-dependent passive range of motion looking for a spastic catch, spasticity, and clonus, and evaluation of gait were the most frequently used physical evaluations. The most frequently used spasticity tools were the Modified Ashworth Scale, goniometer, and Goal Attainment Scale. Results were similar in brain- and spinal cord-predominant etiologies. To evaluate goals, qualitative description was used most (37.5%). CONCLUSION: Our findings provide a better understanding of the spasticity management landscape in Canada with respect to staffing, physical evaluations, and outcome measurements used in clinical practice. For all etiologies of spasticity, visual observation of patient movement, Modified Ashworth Scale, and qualitative goal outcomes descriptions were most commonly used to guide treatment and optimize outcomes. Understanding the current practice of spasticity assessment will help provide guidance for clinical evaluation and management of spasticity.

Recommendations for Ultrasound Guidance for Diagnostic Nerve Blocks for Spasticity. What Are the Benefits?

The diagnostic nerve block (DNB) for spasticity is the percutaneous application of an anesthetic to an individual peripheral nerve trunk (mixed motor sensory nerve), nerve branch to a muscle or an intramuscular branch. The DNB causes a temporary paralysis to assess the contribution of muscle(s) on the spastic pattern and may unmask a fully or partially increased joint range of motion. The anesthetic literature supports the use of ultrasound (US) guidance to improve nerve blocks for sensory targets. This communication summarizes the potential advantages that support the use of US to improve DNB technique. Nerves are much smaller than muscle targets and have various known innervation patterns. US allows for rapid localization of the target before injection, particularly in complex anatomy patterns. The nerve trunks are typically found adjacent to or encapsulating blood vessels, which can be quickly identified with or without color Doppler, allowing the clinician to scan from the vessels to the target and avoid intravascular injection. Lower stimulation levels can be used as the targeted muscle(s) can be seen stimulating rather than only on the surface. A shorter needle insertion time and lower stimulation levels should cause less discomfort to the patient. Smaller volumes of anesthetic may be used as the fluid is seen reaching its target and cessation of stimulation is observed. Further study is needed to identify evidence supporting US utilization with electrical stimulation in DNBs for spasticity management, as US use during nerve blocks for perineurial anesthesia has demonstrated improved patient safety and procedural efficiency.

International Recommendations to Manage Poststroke Equinovarus Foot Deformity Validated by a Panel of Experts Using Delphi.

OBJECTIVE: To establish international recommendations for the management of spastic equinovarus foot deformity. DESIGN: Delphi method. SETTING: International study. PARTICIPANTS: A total of 24 international experts (N=24) in neuro-orthopedic deformities, from different specialties (Physical and Rehabilitation Medicine physicians, neurologists, geriatricians, orthopedic surgeons, neurosurgeons, plastic surgeons). INTERVENTIONS: Experts answered 3 rounds of questions related to important aspects of diagnosis, assessment, and treatment of spastic equinovarus foot deformity. MAIN OUTCOME MEASURES: A consensus was established when at least 80% of experts agreed on a statement RESULTS: A total of 52 items reached consensus. Experts recommend assessing effect of the deformity on functional activities before treatment. Before treatment, it is crucial to differentiate spastic muscle overactivity from soft tissue contractures, identify which muscles are involved in the deformity, and evaluate the activity of antagonist muscles. Motor nerve blocks, 2-dimensional video analysis, and radiologic examinations are often required to complement a clinical examination. The treatment of equinovarus foot depends on the correctability of the deformity and the patient's ability to stand or walk. The preoperative assessment should include an interdisciplinary consultation that must finalize a formal agreement between physicians and the patient, which will define personalized attainable goals before surgery. CONCLUSION: The establishment of guidelines on managing equinovarus foot will help physicians and surgeons, specialists, and nonspecialists to diagnoses and assess the deformity and direct patients to a network of experts to optimize patient functional recovery and improve their autonomy.

Ischemic Monomelic Neuropathy: The Case for Reintroducing a Little-Known Term.

Ischemic monomelic neuropathy (IMN) is a little-known, painful axonal neuropathy, secondary to vascular occlusion or steal phenomenon. It typically occurs after vascular bypass, hemodialysis fistulization, or diabetic microvascular disease in the absence of significant clinical features of ischemia. There is limited literature to assist in the characterization and diagnosis of this condition. We describe three patients with IMN with no surgical or peripheral vascular disease history who exhibited spontaneous, persistent foot pain, edema numbness, and weakness with denervation on needle electromyogram in a distal lower leg peripheral nerve distribution. Occlusive disease was found in all patients on angiogram, requiring vascular bypass surgery.

Access to Focal Spasticity Care: A Cross Canada Survey of Physiatrists.

Successful management of focal spasticity requires access to botulinum toxin type A (BoNT-A) injections, physiotherapy, occupational therapy, and orthoses/bracing. To assess the quality of focal spasticity care across Canada, we sent a survey consisting of 22 questions to physiatrists involved in the management of outpatient spasticity. Thirty-four physiatrists from all 10 provinces responded to the survey. Wait time for BoNT-A treatment averaged 12.7 weeks from time of referral across Canada. More than 75% of patients faced barriers to obtaining physical therapy and orthoses. Access to best quality care for spasticity patients across Canada varies widely.

A Delphi-Based Consensus Statement on the Management of Anticoagulated Patients With Botulinum Toxin for Limb Spasticity.

OBJECTIVE: To create a consensus statement on the considerations for treatment of anticoagulated patients with botulinum toxin A (BoNTA) intramuscular injections for limb spasticity. DESIGN: We used the Delphi method. SETTING: A multiquestion electronic survey. PARTICIPANTS: Canadian physicians (N=39) who use BoNTA injections for spasticity management in their practice. INTERVENTIONS: After the survey was sent, there were e-mail discussions to facilitate an understanding of the issues underlying the responses. Consensus for each question was reached when agreement level was ≥75%. MAIN OUTCOME MEASURES: Not applicable. RESULTS: When injecting BoNTA in anticoagulated patients: (1) BoNTA injections should not be withheld regardless of muscles injected; (2) a 25G or smaller size needle should be used when injecting into the deep leg compartment muscles; (3) international normalized ratio (INR) level should be ≤3.5 when injecting the deep leg compartment muscles; (4) if there are clinical concerns such as history of a fluctuating INR, recent bleeding, excessive or new bruising, then an INR value on the day of injection with point-of-care testing or within the preceding 2-3 days should be taken into consideration when injecting deep compartment muscles; (5) the concern regarding bleeding when using direct oral anticoagulants (DOACs) should be the same as with warfarin (when INR is in the therapeutic range); (6) the dose and scheduling of DOACs should not be altered for the purpose of minimizing the risk of bleeding prior to BoNTA injections. CONCLUSIONS: These consensus statements provide a framework for physicians to consider when injecting BoNTA for spasticity in anticoagulated patients. These consensus statements are not strict guidelines or decision-making steps, but rather an effort to generate common understanding in the absence of evidence in the literature.

Electrodiagnostic Testing and Treatment for Carpal Tunnel Syndrome in Canada.

OBJECTIVES: 1) Assess which electrodiagnostic studies Canadian clinicians use to aid in the diagnosis of carpal tunnel syndrome (CTS). 2) Assess whether Canadian clinicians follow the American Association of Neuromuscular & Electrodiagnostic Medicine/American Academy of Neurology/American Academy of Physical Medicine and Rehabilitation Practice Parameter for Electrodiagnostic Studies in CTS. 3) Assess how Canadian clinicians manage CTS once a diagnosis has been established. METHODS: In this prospective observational study, an electronic survey was sent to all members of the Canadian Neuromuscular Group (CNMG) and the Canadian Association of Physical Medicine and Rehabilitation (CAPM&R) Neuromuscular Special Interest Group. Questions addressed which electrodiagnostic tests were being routinely used for the diagnosis of carpal tunnel syndrome. Management recommendations for CTS was also explored. RESULTS: Of the 70 individuals who completed the survey, fourteen different nerve conduction study techniques were reported. Overall, 36/70 (51%) of participants followed the AANEM/AAN/AAPM&R Practice Parameter. The standard followed by the fewest of our respondents with 64% compliance (45/70) was the use of a standard distance of 13 to 14 cm with respect to the median sensory nerve conduction study. Regarding management, 99% would recommend splinting in the case of mild CTS. In moderate CTS, splinting was recommended by 91% of clinicians and 68% would also consider referral for surgery. In severe CTS, most recommended surgery (93%). CONCLUSIONS: There is considerable variability in terms of which electrodiagnostic tests Canadian clinicians perform for CTS. Canadian clinicians are encouraged to adhere to the AANEM/AAN/AAPM&R Practice Parameter for Electrodiagnostic Studies in CTS.

Spasticity Treatment Beyond Botulinum Toxins.

Botulinum toxin (BonT) is the mainstream treatment option for post-stroke spasticity. BoNT therapy may not be adequate in those with severe spasticity. There are a number of emerging treatment options for spasticity management. In this paper, we focus on innovative and revived treatment options that can be alternative or complementary to BoNT therapy, including phenol neurolysis, cryoneurolysis, and extracorporeal shock wave therapy.

Cryoneurolysis for the Treatment of Knee Arthritis to Facilitate Inpatient Rehabilitation: A Case Report.

A 65-year-old woman presenting with a sensory ganglionopathy complicated with COVID-19 is limited in her rehabilitation due to pain from lateral compartment knee osteoarthritis. To increase participation in rehabilitation, cryoneurolysis of the medial and lateral anterior femoral cutaneous nerve and infrapatellar branches of the saphenous nerve was provided to manage pain associated with knee osteoarthritis. The patient reported immediate relief from pain. Physiotherapy noted improvement immediately after the procedure. Follow-ups at 7- and 11-days post-treatment revealed ongoing increases in mobility and reduction in pain. The patient was discharged to live independently shortly after cryoneurolysis. Cryoneurolysis for knee osteoarthritis could be considered as a treatment option to increase participation in rehabilitation for hospital inpatients who are stalled in their rehabilitation due to pain and poor mobility from knee osteoarthritis.

Cryoneurolysis of the Femoral Nerve for Focal Spasticity in an Ambulatory Patient.

Introduction: Spasticity of the knee extensors is a common presentation among patients with multiple sclerosis. The resulting stiff leg gait can result in increased risk of falls, heightened energy expenditure during gait, lowered gait speed, and compensatory gait mechanisms that increase wear on the hips. Cryoneurolysis is a novel percutaneous, minimally invasive treatment for focal spasticity. Methods: A single patient with multiple sclerosis was treated with cryoneurolysis of the femoral nerve branch to rectus femoris. The patient was followed for 15 months. Spasticity severity, gait speed, and patient reported outcomes were collected at each follow-up. Results: Spasticity severity as per the Modified Ashworth Scale was reduced at 1 month, with change persisting up to 15 months post-procedure. Range of motion as per the Modified Tardieu Scale showed gradual improvement over the 15-month period. Gait speed increased after the procedure from 21.15 seconds to 12.49 seconds for the 10 m walk test 1 month post-procedure, then slowed to baseline after 15 months. The patient's confidence in their gait improved and their independence was maintained throughout the follow-up period. Because of the regression in the 10 m walk test, the patient elected to have the procedure repeated after 15 months. Immediately after the procedure, the 10 m test time improved to 16.20 seconds. Conclusion: Cryoneurolysis of the femoral nerve may be an effective, long-lasting treatment for spasticity causing stiff knee gait in patients with multiple sclerosis.

Bilateral Suprascapular Nerve Cryoneurolysis for Pain Associated With Glenohumeral Osteoarthritis: A Case Report.

Osteoarthritis is a leading cause of disability, typically treated with exercise, analgesics, injections, or surgeries. Cryoneurolysis is an established technique for the treatment of pain, including osteoarthritis that may provide an alternative for patients in whom surgery is not appropriate and conservative measures have failed. We present our experience with a 78-year-old man with severe pain from bilateral glenohumeral osteoarthritis. Their condition is complicated by several concurrent diagnoses, leaving them ineligible for surgical intervention, despite pharmacologic treatments proving insufficient to manage their pain. As an alternative, bilateral cryoneurolysis of the suprascapular nerve was performed at the suprascapular notch. Pain and disability scores both lessened on the Brief Pain Inventory Score, Disabilities of the Arm Shoulder and Hand (change of 9 points after 170 days) as well as the Shoulder Pain and Disability Index (change of 19 points after 170 days). The patient had improved active and passive range of motion for flexion, abduction, and external rotation of the shoulder. Improvements endured to follow-up at 170 days. There were no negative side effects as a result of the procedure.

A retrospective review of the management and outcomes of patients diagnosed with complex regional pain syndrome type II using electrodiagnostic findings.

Objectives: The objective of this study was to assess the outcomes of the use of electrodiagnosis in the diagnosis and management of discrete nerve injuries in patients with complex regional pain syndrome (CRPS). Design: This study is a secondary retrospective cohort analysis of patients diagnosed with CRPS from a single outpatient physical medicine and rehabilitation clinic and included all patients who had abnormal electrodiagnostic findings, in addition to CRPS. Results: Sixty patients of 248 diagnosed with CRPS underwent electrodiagnosis, 41 of whom had abnormal electrodiagnostic findings indicating a discrete nerve injury. Only 51% of the 41 referrals had indicated the suspicion of a nerve injury. Nearly all patients had undergone physiotherapy. Forty-one percent responded to treatment with oral prednisone alone, 54% had a functional improvement after a combination of treatments including corticosteroids, and 5% improved with treatments that did not involve corticosteroids. Surgical interventions for nerve injuries were required for 34% of patients in the cohort. All surgeries involved the median or ulnar nerve, with the exception of one fibular nerve. After treatment, 39 of 41 patients had functional recoveries or better. Conclusions: Electrodiagnosis can inform diagnosis of nerve injury and direct intervention including the need for surgical intervention. Electrodiagnosis should be considered for patients with initial signs of concomitant discrete nerve injury or with CRPS who are not responding to treatments because a nerve injury may be underlying.What is Known Complex Regional Pain Syndrome (CRPS) is a poorly understood pain condition. CRPS has been divided into two subtypes, the second subtype involves a discrete nerve injury with pain that extends beyond the territory of the nerve injury.What is New We observed that nerve injuries that may require surgical intervention are diagnosed just over half of the time upon initial assessment in patients with suspected CRPS. We observed that nerve injuries frequently required specifically directed interventions in place of or in conjunction with CRPS treatments. We suggest that electrodiagnosis is an important part of the triage protocol for CRPS II to reveal discrete nerve injuries that may be hidden. We recommend that electrodiagnosis be considered for patients with initial signs of concomitant discrete nerve injury or for CRPS patients who do not improve with medical therapies.

CRPS typically occurs after an injury or inciting event and can be accompanied by severe pain, sensitivity, swelling, changes in the color of the skin, changes in the texture of the skin, changes in hair and nail growth, weakness, muscle wasting, range of motion reduction, and temperature changes in the affected area. Little is known about type II CRPS, which may present with all of the same signs and symptoms as above but with damage to a nerve in the area. This study examined cases of CRPS where patients had electrodiagnostic findings that suggested a nerve injury. We found that the referring physicians reported nerve injuries in just over half of the cases. Oral prednisone was often the chosen treatment for these patients, although many required additional treatments, including surgery, to address their nerve injury. We recommend that electrodiagnosis be considered for patients with CRPS who are not responding to corticosteroids because a nerve injury could be preventing CRPS symptoms from resolving. When the CRPS trigger was a trauma that likely simultaneously injured the nerve, patients needed to have surgery more frequently than those with atraumatic onsets.

A Case Report of Cryoneurolysis for Dorsal Foot Pain and Toe Clawing in a Patient With Multiple Sclerosis.

Toe clawing in patients with upper motor neuron disorders is often attributed to the flexor digitorum longus (FDL) and is a common presentation among patients with multiple sclerosis (MS). This movement may be painful because of the altered pressure distribution and may increase the risk of falls, heighten energy expenditure during gait, and lower gait speed. Cryoneurolysis is a minimally invasive treatment that may be beneficial for pain and focal muscle hypertonicity. An ambulatory patient with MS was treated bilaterally with cryoneurolysis to the superficial fibular nerves for pain on the dorsum of the foot, and to the intramuscular tibial nerve motor branch to FDL for toe clawing. The patient felt that toe clawing was immediately reduced during gait and noted the ability to voluntarily spread their toes. The patient stated that the neuropathic pain on the dorsum of the foot was fully eliminated immediately post procedure. The patient reported improved confidence in their gait, maintained independence, and reduced toe clawing during a structured interview 12 weeks after treatment. The effects lasted for 5.5 months before symptoms returned. Retreatment at 6 months reproduced the benefits. The patient reported a positive experience with cryoneurolysis for toe clawing and dorsal foot pain.

A Case Report Illustrating the Combined Use of Cryoneurolysis and Percutaneous Needle Tenotomy in the Treatment of Longstanding Spastic Shoulder Contractures After Stroke.

Adduction and internal rotation of the shoulder is a common presentation in post-stroke patients, and can often be caused by spasticity and musculotendinous retraction causing a contracture of the pectoralis major and minor muscles. A post cerebral arteriovenous malfunction rupture patient with severe refractory left shoulder spasticity with contracture was treated with cryoneurolysis to the medial and lateral pectoral nerves, combined with a percutaneous needle tenotomy to the pectoralis major tendon. There was an improvement in shoulder forward flexion, abduction and external rotation immediately and found sustained at 8 weeks by 50°, 45°, and 15°. The patient noted an immediate cessation of limitation of shoulder abduction, a liberation of range of motion of the shoulder, and looseness in their arm and shoulder. They reported a dramatic improvement in their gait, increased independence, and an improvement in overall quality of life in a structured interview 8 weeks after the procedure. The patient relayed a positive experience with the combined neuro-orthopedic procedure of cryoneurolysis and tenotomy for the treatment of their spastic shoulder. This combined treatment could be considered as a management strategy for patients experiencing shoulder spasticity with contracture.

Canadian Physicians' Use of Intramuscular Botulinum Toxin Injections for Shoulder Spasticity: A National Cross-Sectional Survey.

Spasticity of the upper extremity can result in severe pain, along with many complications that can impair a patient's activities of daily living. Failure to treat patients with spasticity of the upper limb can result in a decrease in the range of motion of joints and contracture development, leading to further restriction in daily activities. We aimed to investigate the practice patterns of Canadian physicians who utilize Botulinum toxin type-A (BoNT-A) injections in the management of shoulder spasticity. 50 Canadian Physical Medicine and Rehabilitation (PM&R) physicians completed a survey with an estimated completion rate of (36.23%). The demographics of the survey participants came from a variety of provinces, clinical settings, and patient populations. The most common muscle injected for shoulder adduction and internal rotation spasticity was the pectoralis major, this was followed by latissimus dorsi, pectoralis minor, subscapularis and teres major. Injection of BoNT-A for problematic post-stroke shoulder spasticity was common, with (81.48%) of participants responding that it was always or often used in their management of post-stroke spasticity (PSS). Dosing of BoNT-A demonstrated variability for the muscle injected as well as the type of toxin used. The goals of the patients, caregivers, and practitioners were used to help guide the management of these patients. As a result, the practice patterns of Canadian physicians who treat shoulder spasticity are varied, due to numerous patient factors. Future studies are needed to analyze optimal treatment patterns, and the development of algorithms to standardize care.

Analysis of Adverse Effects of Cryoneurolysis for the Treatment of Spasticity.

OBJECTIVE: The aim of the study is to report adverse effects from clinical studies on ultrasound-guided percutaneous cryoneurolysis for spasticity. DESIGN: Patients were prospectively enrolled in three studies at a single institution. Cryoneurolysis was performed to primarily motor nerve branches (medial and lateral pectoral, musculocutaneous, radial, median, ulnar, tibial, obturator) and mixed motor sensory nerve trunks (median, ulnar, suprascapular, radial, and tibial). RESULTS: Cryoneurolysis was performed for 277 nerves (99 mixed motor sensory), on 113 patients (59 F, 54 M, average age 54.4 yrs). One patient had a local skin infection and two patients had bruising or swelling; all resolved within 1 mo. Nine reported nerve pain or dysesthesia (two motor, seven mixed motor sensory nerves). Four received no treatment, four oral or topical medications, two perineural injections, one botulinum toxin. Three patients' symptoms remained until 3 mos and one had numbness at six. One patient had botulinum toxin injections for cramping. All had at minimum 3-mo follow-up; seven withdrew (x̄ = 5.4 mos), four passed away. None of these 11 reported adverse effects. CONCLUSIONS: A total of 96.75% of nerve treatments had no pain or dysesthesias beyond treatment. Few had pain or numbness beyond 3 mos. Cryoneurolysis has potential to be a safe spasticity treatment with manageable adverse effects.

Reduction of neutrophil extracellular traps accelerates inflammatory resolution and increases bone formation on titanium implants.

Neutrophils are the most abundant immune cells in the blood and the first cells to be recruited to the biomaterial implantation site. Neutrophils are fundamental in recruiting mononuclear leukocytes to mount an immune response at the injury site. Neutrophils exert significant pro-inflammatory effects through the release of cytokines and chemokines, degranulation and release of myeloperoxidase (MPO) and neutrophil elastase (NE), and the production of large DNA-based networks called neutrophil extracellular traps (NETs). Neutrophils are initially recruited and activated by cytokines and pathogen- and damage-associated molecular patterns, but little is known about how the physicochemical composition of the biomaterial affects their activation. This study aimed to understand how ablating neutrophil mediators (MPO, NE, NETs) affected macrophage phenotype in vitro and osseointegration in vivo. We discovered that NET formation is a crucial mediator of pro-inflammatory macrophage activation, and inhibition of NET formation significantly suppresses macrophage pro-inflammatory phenotype. Furthermore, reducing NET formation accelerated the inflammatory phase of healing and produced greater bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration. Our findings emphasize the importance of the neutrophil response to implanted biomaterials and highlight innate immune cells' regulation and amplification signaling during the initiation and resolution of the inflammatory phase of biomaterial integration. STATEMENT OF SIGNIFICANCE: Neutrophils are the most abundant immune cells in blood and are the first to be recruited to the injury/implantation site where they exert significant pro-inflammatory effects. This study aimed to understand how ablating neutrophil mediators affected macrophage phenotype in vitro and bone apposition in vivo. We found that NET formation is a crucial mediator of pro-inflammatory macrophage activation. Reducing NET formation accelerated the inflammatory phase of healing and produced greater appositional bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration.