The purpose of this study is to determine the effectiveness and safety of autologous alpha-2 macroglobulin rich plasma (A2MRP) injections in the treatment of knee osteoarthritis (OA).

The overall objective of this study is to test and quantify A2MRP and prepare for a larger randomized clinical trial assessing the efficacy of A2MRP injections in primary and post traumatic knee osteoarthritis (OA) with respect to clinical outcomes and disease progression. The study will also assess safety of A2MRP intraarticular injection in patients with symptomatic knee OA. Patients with symptomatic mild to moderate knee OA (KL 2-3) will be candidates for this study. Baseline data will include physical examination of the knee, clinical assessment of knee pain and function using validated patient reported outcome measures (PROMs), and radiologic exam of the knee will be obtained. All injections will be performed using ultrasound guidance and all patients will followed-up at week 1 week post-injection for acute adverse events (AEs). Each subject will be clinically followed-up for study endpoints using a predetermined protocol. PROs will be collected during the study period pre-procedure, and at 1, 2, and 6 weeks, 3-, 6-, 9- and 12-months post-procedure (Specific PRO's and timepoints noted in sections 6.2-6.7). Subjects will also be asked questions regarding satisfaction with the treatment and whether they would recommend the treatment

Inclusion Criteria:

1. Male or females,18-65 years of age
2. Chronic (> 3 months), unilaterally symptomatic, primary knee OA.
3. Painful knee OA in one or more knee compartments grade 2-3 radiologic severity based upon the Kellgren-Lawrence grading scale, without evidence of advanced (bone on bone, as determined by study investigators) OA in the patellofemoral compartment or on Posterior Anterior (PA) flexion views
4. Cognitive ability to give informed consent
5. Speak fluent English
6. Worst knee pain greater than 4 on a 0-10 pain scale (0 = no pain, 10 = worst pain imaginable)
7. Previous 6 week or longer trial of one of the following conservative treatments: activity modification, weight loss, physical therapy, anti-inflammatory medications/acetaminophen or injection therapy (e.g., cortisone)
8. Fully understanding of the requirements of the study and willingness to comply with the treatment plan, including blood draw, laboratory tests, diagnostic imaging, and follow-up visits and assessments
9. Can provide written informed consent and complete HIPAA documentation after the nature of the study is fully explained and prior to any study-related procedure.

Exclusion Criteria:

1. Pregnant or nursing, or planning on becoming pregnant during the study period

2. Congenital or acquired malformation of the target knee resulting in significant deformity or leading to problems with the study treatment or analysis of the results

3. Significant valgus or varus malalignment as determined by investigator

4. Injections of any kind into the target knee:

   • Corticosteroid injections within 3 months prior to study enrollment
   • Hyaluronic acid injections within 6 months prior to study enrollment
   • PRP injection within the year prior to study enrollment
   • History of BMAC, Micro-Fragmented Adipose Tissue (MFAT), or perinatal product injection at any point

5. History of intra-articular infection in the target knee

6. History of superficial infection in the target knee within 6 months of study enrollment, or evidence of current superficial infection affecting the target knee

7. Body mass index (BMI) < 35 kg/m2

8. Inability to stop non-steroidal anti-inflammatory medications for 1 week before through 2 weeks after the procedure date

9. On chronic, immunosuppressive transplant therapy or having a chronic, immunosuppressive state, including use of systemic steroids/corticosteroids

10. Current tobacco product use, including nicotine patch or other nicotine products

11. Clinically significant rheumatological or inflammatory disease or chondrocalcinosis/ calcium pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, systemic sclerosis, system lupus erythematosus, and Ehlers-Danlos Syndrome, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis

12. Surgery in the target knee within the last 12 months, or planned surgery in the target knee in next 12 months