Inclusion Criteria:
1. Age 17 to 65 at the time of planned randomization visit (Visit 2).
2. One or more symptomatic chondral or osteochondral lesion/s as defined by FAOS Pain score ≤ 50 and FAOS Function (SRA) score ≤ 50.
3. International Cartilage Repair Society (ICRS) Score Grade 3 or 4 chondral or osteochondral lesion/s located on the talus with or without cysts, including shoulder lesions (lesions on the talar neck), and amenable to treatment with the surgical procedure specified at randomization.
4. At least 1 lesion ≥ 1.2 cm².
5. Written informed consent and assent (as applicable) per Institutional Review Board (IRB) requirements.
6. Participant will refrain from using Non-steroidal Anti-inflammatory Drugs (NSAIDS) for 12 weeks post-study treatment. (Post-surgical use of low-dose aspirin for clot prevention is acceptable).
7. Participant will restrict pain medication to over-the-counter analgesics (NSAIDs or acetaminophen/paracetamol) after 12 weeks post-study treatment.
8. Participant must have Hematocrit ≥30.0%; White Blood Cell count ≤14,000 cells/μL; Platelet Count ≥50,000 platelets/μL; Creatinine ≤2.0 mg/dL; and International Normalized Ratio (INR) ≤1.6.
Exclusion Criteria:
1. Lesions with an underlying bony defect depth of \> 5 mm.
2. Any surgery on the target joint within 24 weeks prior to Visit 1 (not including diagnostic ankle arthroscopy).
3. Previous investigational drug, biologic or device use within 12 weeks prior to Visit.
4. Avascular necrosis of the target ankle.
5. Symptomatic musculoskeletal conditions in the lower limbs that could impede measurement of efficacy for the target ankle joint.
6. Participant with "kissing lesions" (bipolar lesions, involving both the tibia and talus), or with bilateral lesions in both ankles.
7. Participant with lesions that require an osteotomy procedure to allow for MACI implantation as determined at the time of ankle arthroscopy (Visit 2).
8. Concomitant systemic inflammatory diseases or other conditions that affect the joints (e.g., rheumatoid arthritis, metabolic bone disease, psoriasis, symptomatic chondrocalcinosis).
9. History of advanced or severe osteoarthritis of the ankle as determined by prior surgical history confirming no joint space (i.e., "bone on bone") or radiographic evidence of Modified Kellgren-Lawrence Grade 4 arthritis (i.e., osteophytes on lateral and medial malleoli and at the tibiotalar joint margins, narrowing of the joint space width \> 50%, and tibiotalar sclerosis), Van Dijk Grade III (i.e., total or subtotal destruction of the joint space) or the equivalent.
10. Known history of septic arthritis in the target ankle joint within 1 year prior to Visit 1.
11. Current malignancy or treatment for malignancy within the past 5 years prior to Visit 1, excluding non-melanoma skin cancer.
12. Known history of hypersensitivity to gentamicin, other aminoglycosides, or products of porcine or bovine origin.
13. Females who are pregnant or lactating.
14. Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems that warrant exclusion. Examples of significant problems included but are not limited to:
1. Any condition that has potential for negatively impacting intra- or postoperative course (e.g., uncontrolled diabetes, heavy smoking). - Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8.0% and/or fasting plasma glucose \>250 mg/dL (13.9 mmol/L) within the last 90 days prior to Screening Visit 1 - Heavy smoking is defined as current smoker with use of ≥20 cigarettes per day (≥1 pack/day) at the time of Screening Visit 1.
2. Conditions that limit compliance with rehabilitation program.
3. Any condition that has potential for significantly limiting participant's ability to assess postoperative ankle function.
4. Any condition, psychiatric or otherwise, that would preclude informed consent/assent, consistent follow-up, or compliance with any aspect of the clinical trial.
5. Participant is currently abusing drugs or alcohol or, in the opinion of the Investigator, at high risk for poor compliance.
6. Any abnormal screening blood work that the Investigator deems clinically significant in addition to the parameters delineated in Inclusion Criterion #8.
15. Injection of hyaluronic acid (HA), platelet-rich plasma (PRP), and/or corticosteroids in the target ankle within 90 days prior to Visit 1.
