Human ECM Implanted Within Microfracture Interstices & the Cartilage Defect in the Knee to Regenerate Hyaline Cartilage

Inclusion Criteria: \- Age 1. Participant must be ≥ 18 years and ≤ to 50 years of age (18-50), at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Patients who are "healthy" as determined by medical evaluation including medical history, physical exam, laboratory tests, no thyroid conditions, and no history of cancer, etc. 3. Patients with controlled hypertension defined as systolic blood pressure less than 140mmHg and diastolic blood pressure less than 90mmHg. 4. Patients with well controlled diabetes mellitus type 2 defined as an HbA1C of less than 6.5%. 5. Patients that have hematological parameters as follows: hematocrit ≥ 28.0%, white blood cell count ≤ 14,000/mm3, platelet count ≥ 50,000/mm3, creatinine ≤ 2.0mg/dL and International Normalized Ration (INR) ≤ 1.6. 6. Patients that have been diagnosed with a symptomatic (knee pain, effusion, and limitation of activity due to the lesion) cartilage lesion of the medial or lateral femoral condyle and have failed to respond to more conservative pharmacologic or non-pharmacologic treatments. Acute, isolated, traumatic defects are permitted in the study. 7. A cartilage lesion on the medial or lateral femoral condyle that is Grade III or IV on the Outerbridge scale, and having size of 2 cm2 - 4 cm2 as detected by MRI or recent arthroscopy if conducted in connection with this acute knee injury. 8. Intact ligaments - including intact (i) anterior cruciate ligament (ACL), (ii) lateral collateral ligament (LCL), (iii) posterior cruciate ligament (PCL), and (iv) medial collateral ligament (MCL). No concurrent ligament surgery is permitted. 9. Near normal (within 3 degrees of center) hip to ankle coronal alignment on plain radiographs. Per Schedule of Activities, X-ray of knee will be taken at screening visit. 10. Participant who is medically able to undergo knee arthroscopy and participate in the postoperative therapy protocol, including a period (up to 4 to 6 weeks) of nonweight bearing movement. 11. If participant has had prior surgery in the index knee but is stable on exam, then the participant can be included in the study (e.g., stable ACL reconstruction, diagnostic arthroscopy, plica/scar debridement, meniscus debridement less than 50%, and chondroplasty are permitted). No prior microfracture surgery in the index knee are permitted. 12. Tibial lesions on the same side as the femoral condyle lesion being treated up to Grade I or II Outerbridge grade is permitted. 13. Participant is eligible for microfracture surgery (lesion between 2cm2 - 4 cm2, Outerbridge Grade III or IV, intact subchondral plate without bony erosion, and deemed to have a clinically significant cartilage lesion). 14. Participant is able to read/write and understand the language and content of the study material, understand the requirements for follow-up visits, able and willing to comply with requirements, and is willing to provide information at the scheduled evaluations. 15. Participant is willing to use pain medication other than non-steroidal Antiinflammatory Drugs (NSAIDS) (e.g., ibuprofen/Advil and indomethacin may speed cartilage breakdown and is therefore prohibited) for 3 months post-surgery. Other medications (e.g., acetaminophen or narcotic analgesics) are permitted if prescribed. Post-surgical use of aspirin for clot prevention is acceptable (DVT prophylaxis acceptable) for up to 3 weeks (per surgeons standard DVT prophylaxis). 16. Participant has a creatinine clearance of more than 45 ml/min using the Cockcroft- Gault calculation. -Weight 17. Body mass index (BMI) greater than or equal to 18 kg/m2 and less than or equal to 35.0 kg/m2. (If patient is lean and considered healthy, yet exceeds 35.0 kg/m2, then the investigator may enroll up to 40.0 kg/m2 on a case-by-case basis). -Sex 18. All genders are included. -Informed Consent 19. Capable of giving signed informed consent as described in Section 9.1 (Appendix 1) which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. -Inclusion of Women and Minorities in Study 20. This study will admit patients based solely on the inclusion and exclusion criteria. All potential clinical study candidates will be assessed for participation with no consideration to their gender, ethnic background or other non-pertinent classifications other than those described in the inclusion and exclusion criteria. Exclusion Criteria: * Medical Conditions 1. History of substantial (greater than or equal to 50%) meniscal repair or a meniscectomy. 2. Body Mass Index (BMI) of ≥ 35 kg/m2 and \< 18 kg/m2, at the time of screening (see inclusion criteria 17 above). 3. Known, recent (within one month of screening) history of bacterial infection regardless of body location. 4. Prior surgical repair of the site (femoral condyle) intended to undergo microfracture surgery. No prior microfracture of the index knee is permitted. 5. Single Assessment Numeric Evaluation (SANE) of greater than 80. 6. Prior surgery of the contralateral knee within the last 3 months (since opposite knee needs to be intact for the non-weightbearing period post-op). 7. Known kidney impairment, for which contrast agents for MRI could add to risks (see inclusion 16 and exclusion 13). 8. Has vascular disorders such as varicose veins or peripheral arterial disease or neurological disorders (e.g., neuropathy affecting the index lower limb). 9. Known allergy to anesthetics used in the study. 10. Presence of significantly uncontrolled hypertension defined as systolic blood pressure more than or equal to 140mmHg and diastolic blood pressure more than or equal to 90mmHg. 11. Severely uncontrolled diabetes mellitus, defined as HbA1C of 6.5% or more. 12. Patients with results from any of the screening blood work to include: complete blood count, Prothrombin Time (PT)/Partial Thromboplastin Time (PTT)/INR, liver function, and creatinine) that exceeds 1.5 times the upper limit of normal or below 0.5 times the lower limit of normal. 13. Patients with significant renal or hepatic impairment, as indicated by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) greater than (\>) 3 times the upper limit of normal (ULN); total bilirubin \>1.5 times ULN (except in case of Gilbert's syndrome); creatinine \>1.5 times ULN; hemoglobin less than (\<5.5) millimole per liter (mmol/L), white blood cell count (WBC) \<2.5 \* 10\^9 per liter, or platelets \<75 \*10\^9 per liter). 14. Recent (within 1 year from screening) history of thromboembolism. 15. Known heart failure New York Heart Association (NYHA) class III or higher. 16. Current malignancy or treatment for malignancy within the past 5 years, with the exception of non-melanoma skin cancer, or carcinoma in situ events. 17. History of smoking (tobacco and e-cigarettes) for the previous year. No smoking throughout the trial. 18. Known or planned pregnancy. 19. Known allergies to rice (the recombinant human serum albumin used in the manufacturing process is produced in rice) and history of allergy to gadolinium or other contrast reagents, severe unspecified allergies or anaphylaxis. 20. Medical conditions associated with immune suppression or medications that represent immune suppressants. 21. Likely to need or who are currently on systemic steroids. 22. Any other abnormal laboratory results or significant medical conditions that the Investigator believes should preclude the subject's participation in the trial. 23. Prior surgical treatment of the index knee that remain unstable on exam, as determined by the investigator, are not permitted. Prior microfracture surgery or meniscectomy (either or both meniscus) of greater than 50% are excluded. 24. No bone loss, no cortical disruption on MRI. 25. Joint space narrowing of less than 3 mm on weight bearing flexion PA and standard PA radiographs. No evidence of osteophytes or significant subchondral sclerosis. 26. History or any signs of systemic arthritis, including rheumatoid, psoriatic, ankylosing spondylitis, or other inflammatory conditions. 27. History of or current evidence of alcohol or illicit drug dependence. 28. Evidence on MRI of PVNS (pigmented villonodular synovitis), neoplasm, or other synovial disease. 29. Patients unable to undergo an MRI with contrast agents or standing radiographs. 30. History of autoimmune disease, allergic or anaphylactic disorders, hepatitis, or HIV or recent COVID-19 exposure as defined by likely exposure due to proximity to COVID-19 positive individuals and/or positive diagnosis by RT-PCR. 31. Participant receiving therapy with anti-coagulants (including aspirin prior to surgery, heparin, coumadin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, or fondaparinux) or receiving anti-platelet agents such as clopidogrel (Plavix). 32. Has received intra-articular injection of corticosteroids, viscosupplements, PRP or stem cell therapies within the last 3 months. Prior/Concurrent Clinical Study Experience 33. Current enrollment in an investigational drug or device study or participation in such a study within 30 days before enrollment. Other Exclusions 34. Females with a positive pregnancy test. 35. Is an employee of the PI/TI/EI/site or study team. Or is an employee or representative of Histogen, or a relative residing with one of the above persons. 36. Has a condition or is in a situation which, in the TI's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant's participation in the study. 37. Has existing comorbidities requiring medication management either continuous or intermittent that could confound the safety and efficacy of the product. 38. Participant is currently receiving worker's compensation or disability or is in litigation for worker's compensation or disability claims.