Our cumulative research efforts for the last 18 years supported by NIH have resulted in successful purification and characterization of a unique extracellular matrix, termed HC-HA/PTX3, from human amniotic membrane and umbilical cord. These research efforts disclose that HC-HA/PTX3, a complex formed by heavy chain 1 covalently linked to hyaluronan (HA) and further complexed with pentraxin 3 (PTX3), singly can orchestrate a broad-spectrum anti-inflammatory action by targeting neutrophils, macrophages, and lymphocytes. HC-HA/PTX3 also exerts a direct anti-scarring action by suppressing canonical TGF-b signaling and such an anti-scarring action is coupled by reprogramming of differentiated fibroblasts into (neural crest) progenitor cells. Furthermore, HC-HA/PTX3 supports niche cells to maintain stem cell quiescence via activation of BMP signaling but suppression of Wnt signaling. New evidence also emerges to support the notion that the aforementioned collective actions mediated by HC-HA/PTX3 may also help promote nerve regeneration, suppress nociceptive pain signaling, and augment vasculogenesis. Therefore, for the first time, a new platform technology is developed based on HC-HA/PTX3-containing birth tissue to deliver regenerative healing that can be translated to a number of clinical benefits ranging from prevention of wound complications, expedited functional recovery, reduction of readmission, and a non-opioid alternative for pain management. The current FDA regulatory status and clinical trials of this new regenerative therapy based on the birth tissue will be presented. It is envisioned that this matrix-based regenerative therapy is promising and can further compliment with stem cell based therapy to promote regenerative healing.