Phase 2B Micronized DHACM vs. Saline in the Treatment of Knee Osteoarthritis

Inclusion Criteria: 1. Subject is age ≥ 21 and ≤ 80 years. 2. Subject has a diagnosis of primary OA of the target knee (as per American College of Rheumatology clinical and radiological criteria) with OA symptoms (as reported by the subject) that have been present for at least 6 months prior to Screening. 3. Subject has Grade 2 or 3 OA of the target knee on the Kellgren Lawrence (KL) grading scale as evaluated by central reading of screening X-ray. 4. Subject is willing and able to provide informed consent and participate in all procedures and follow-up evaluations necessary to complete the study. 5. Subject must have a WOMAC pain score ≥ 4 and ≤ 9 out of 10 in target knee, at screening and baseline. 6. Subject must have tried and failed to adequately respond to 2 knee OA standard of care (SOC) therapies, including at least one pharmacological treatment, for a minimum of 3 months. SOC for knee OA include non-pharmacological (exercise, weight loss, knee braces, cane) and pharmacological treatments (topical nonsteroidal anti-inflammatory drugs \[NSAIDs\], oral NSAIDs, and intra-articular corticosteroids). 7. Subject must be willing to discontinue all current pain medications (including but not limited to oral, topical, intra-articular) during the duration of the study except for acetaminophen (paracetamol) which will be allowed as rescue, except as noted in inclusion criterion 10 below. Limited use of NSAIDS will be permitted at the discretion of the investigator for post injection pain only. 8. Subject must have a WOMAC pain subscale score in contralateral knee less than 4 out of 10, at screening and baseline visits. 9. Subject who is identified as having taking analgesics at their initial screening visit 1a must be willing to abstain from analgesics for a washout period of 5 half-lives of the analgesic plus 48 hours and return for screening visit 1b where WOMAC pain can be collected analgesic-free. 10. Subject must be willing to abstain from use of rescue medication (acetaminophen/paracetamol) for at least 72 hours prior to all study visits subsequent to screening. 11. For male subjects: 1. Subject must agree to use highly effective contraception throughout the study. 2. Subject must agree not to donate sperm during the study. 12. For female subjects: 1. Subject is surgically sterile; or 2. Has been amenorrheic for at least 1 year and is over the age of 55 years; or 3. Has a negative urine pregnancy test and agrees to use acceptable contraceptive measures (e.g. hormonal contraceptives, barriers with spermicide, intrauterine device or vasectomized partner) from the time of informed consent through the end of the study; and 4. Must commit to the use of highly effective form of birth control from the time of informed consent through the end of the study. 13. Subject must have vital signs within the following ranges at the screening visit and at the baseline visit before investigational product administration: 1. Systolic blood pressure ≤140 and ≥90 mmHg, 2. Diastolic blood pressure ≤90 and ≥60 mmHg, 3. Heart rate \<100 and \>60 bpm, 4. Temperature: normal, 5. Respiratory rate \<20 and \>12 /min. Exclusion Criteria: 1. Subject has Grade 1 or 4 OA of the target knee on the Kellgren Lawrence (KL) grading scale as evaluated by central reading of screening X-ray. 2. Subject has a BMI greater than 40 kg/m\^2. 3. Subject has a clinical effusion (3+) of the target knee according to the Stroke Test grading system. 4. Subject has symptoms of locking, intermittent block to range of motion, or loose body sensation that could indicate meniscal displacement or an intra-articular loose body. 5. Subject has any active infection of the target knee, and/or any active systemic or local infection. 6. Subject has a history of allergy or sensitivity to any of the investigational product components, including aminoglycoside antibiotics. 7. Symptomatic pain in either or both hips that exceeds that of the target knee, as determined by investigator assessment. 8. Significant radicular back pain, as determined by investigator assessment. 9. Subject has rheumatoid arthritis, psoriatic arthritis, or has been diagnosed with any other disorder that is the primary source of their knee pain, including but not limited to: osteonecrosis, radiculopathy, bursitis, tendinitis, tumor, cancer. 10. Subject has documented history of gout or pseudogout. 11. Subject has fibromyalgia or any other chronic pain disorder. 12. Subject has an autoimmune disease or a known history of having acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV). 13. Subject has received any of the following to the target knee: 1. Intra-articular hyaluronic acid (HA) injection within 24 weeks prior to screening; 2. Intra-articular short-acting corticosteroid such as triamcinolone within 12 weeks prior; if long-acting (Zilretta) within 5 months prior to screening; 3. Platelet rich plasma (PRP) injection within 6 months prior to screening; 4. Is planning to receive physical therapy during the study; 5. Has had or is planning to have major surgery or arthroscopy in the target knee within 52 weeks of treatment; 6. History of a total knee arthroplasty. 14. Subject has a history of total knee arthroplasty in the contralateral knee within the last 12 months. 15. Subject has received any prior treatment with tissue engineered or amniotic products, including any MIMEDX product. 16. Subject has used an investigational drug, device, or biologic within 12 weeks or 5 half-lives of the investigational product prior to screening. 17. Subject has been exposed to investigational use of nerve growth factor (NGF) antagonists. 18. Subject uses any opioids to control their pain. 19. Subject is taking a drug with known or suspected immunosuppressive effects. 20. Subject with a history of systemic corticosteroid use within three months of screening and subjects who are likely to need systemic steroids during the study (e.g., poorly controlled asthma, severe COPD). 21. Subject is breast feeding. 22. Subject has had prior radiation therapy to the target or contralateral knee. 23. Subject is currently taking anticoagulant therapy (excluding Plavix or similar or low dose aspirin). 24. Subject has a known or suspected history of alcohol, narcotic or other drug abuse or substance dependence within the past 12 months, prior to screening. 25. Subject has any significant medical or psychiatric condition that, in the opinion of the Investigator, would interfere with protocol evaluation and participation. 26. Subject has any of the following uncontrolled co-morbid conditions: cirrhosis, Child Class B or C liver disease, or other clinically significant indicators of liver disease, such as portal hypertension; eGFR \<60 mL/min/1.73 m\^2 by the CKD-Epi formula; hemoglobin A1c \>8.0 mmol/mol; hemoglobin \<11.0 g/dL; coagulopathy; systolic blood pressure (BP) \>140 or \<90 mmHg, diastolic BP \>90 or \<60 mmHg, or heart rate (HR) ≥100 or ≤60 bpm. 27. Subject has a history of malignancy of any organ system (localized squamous or basal cell carcinoma of the skin are not exclusionary unless localized at the injection site), treated or untreated within 2 years of screening. 28. Subject has a worker's compensation or disability claim related to their knee osteoarthritis. 29. Subject requires more than intermittent use of a rollator, walker, cane, or other assistive devices. 30. Subject currently using marijuana in any form, including but not limited to topical or oral methods of use.